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Receptors Types and details

Receptors are globular proteins located in the cell membrane that receive messages from chemical messengers. When a messenger binds to a receptor's binding site, it causes a conformational change in the receptor through induced fit. This change initiates a signal transduction cascade inside the cell, leading to a cellular response without the messenger entering the cell. The main types of receptors are ion channel receptors, G-protein coupled receptors, kinase-linked receptors, and intracellular receptors. Each triggers distinct downstream signaling pathways through opening ion channels, activating G-proteins, phosphorylating proteins, or regulating gene expression respectively.

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Receptors: Structure and Function
The role of the receptor • Globular proteins • Located mostly in the cell membrane • Receive messages from chemical messengers coming from other cells (CNS) • Transmit a message into the cell leading to a cellular effect • Different receptors specific for different chemical messengers • Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers
The Role of the receptor Cell Nerve Messenger Signal Receptor Nerve Nucleus Cell Response
The Role of the receptor  Neurotransmitters: Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells  Hormones: Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body  Note: Chemical messengers ‘switch on’ receptors without undergoing a reaction
The role of the receptor •Receptors contain a binding site (hollow or cleft on the receptor surface) that is recognised by the chemical messenger •Binding of the messenger involves intermolecular bonds •Binding results in an induced fit of the receptor protein •Change in receptor shape results in a ‘domino’ effect •Domino effect is known as signal transduction, leading to a chemical signal being received inside the cell •Chemical messenger does not enter the cell. It departs the receptor unchanged and is not permanently bound
The Binding Site Cell Membrane Cell Receptor Messenger message Induced fit Cell Receptor Messenger Message Cell Messenger Receptor
The Binding Site • A hydrophobic hollow or cleft on the receptor surface - equivalent to the active site of an enzyme • Accepts and binds a chemical messenger • Contains amino acids which bind the messenger • No reaction or catalysis takes place ENZYME Binding site
The Binding Site • Binding site is nearly the correct shape for the messenger • Binding alters the shape of the receptor (induced fit) • Altered receptor shape leads to further effects - signal transduction Messenge r Induced fit M
How does the Binding Site Change Shape?  Before –  Intermolecular bonds not optimum length for maximum binding strength  After –  Intermolecular bond lengths optimised Phe Ser O H Asp CO2 Induced Fit Phe Ser O H Asp CO2
Induced Fit • Binding interactions must be strong enough to hold the messenger sufficiently long for signal transduction to take place • Interactions must be weak enough to allow the messenger to depart • Implies a fine balance • Designing molecules with stronger binding interactions results in drugs that block the binding site - antagonists M M ER R M ER Signal transduction
Main Types of Receptors • ION CHANNEL RECEPTORS • G-PROTEIN-COUPLED RECEPTORS • KINASE-LINKED RECEPTORS • INTRACELLULAR RECEPTORS
Ion Channel Receptors • Receptor protein is part of an ion channel protein complex • Receptor binds a messenger leading to an induced fit • Ion channel is opened or closed • Ion channels are specific for specific ions (Na+, Ca2+, Cl-, K+) • Ions flow across cell membrane down concentration gradient • Polarises or depolarises nerve membranes • Activates or deactivates enzyme catalysed reactions within cell
Ion Channel Receptors Hydrophilic tunnel Cell membrane Induced fit and opening of ion channel ION CHANNEL (open) Cell Cell membrane MESSENGER Ion channel Ion channel Cell membrane RECEPTOR BINDING SITE Cell Lock Gate Ion channel Ion channel Cell membrane Cell membrane MESSENGER
Ion Channel Receptors Transmembrane Proteins TM2 of each protein subunit ‘lines’ the central pore Protein subunits TM4 TM4TM4 TM3 TM3 TM3 TM3 TM3 TM2 TM2 TM2TM2 TM2 TM1 TM1 TM1 TM1 TM1 TM4 TM4
Gating Five glycoprotein subunits traversing cell membrane MessengerReceptor Induced fit ‘Gating’ (ion channel opens) Binding site Cell membrane Cell membrane
gating • Chemical messenger binds to receptor binding site • Induced fit results in further conformational changes • TM2 segments rotate to open central pore Closed Transverse view TM2 TM2 TM2 TM2 TM2 Cell membrane TM2 TM2 Open Transverse view TM2 TM2 TM2 TM2 TM2
Gating • Fast response measured in msec • Ideal for transmission between nerves • Binding of messenger leads directly to ion flows across cell membrane • Ion flow = secondary effect (signal transduction) • Ion concentration within cell alters • Leads to variation in cell chemistry
• Receptor binds a messenger leading to an induced fit • Opens a binding site for a signal protein (G-protein) • G-protein binds, is destabilised then split messenger G-protein split G-PROTEIN-COUPLED RECEPTORS induced fit closed open
• G-protein subunit activates membrane bound enzyme • Binds to allosteric binding site • Induced fit results in opening of active site • Intracellular reaction catalysed Intracellular reaction active site (closed) active site (open) Enzyme Enzyme G-PROTEIN-COUPLED RECEPTORS
Transmembrane helix C -Terminal chain G-Protein binding region Variable intracellular loop Extracellular loops Intracellular loops N -Terminal chain HO2C NH2 VII VI V IV III II IMembrane G-PROTEIN-COUPLED RECEPTORS
LIGAND BINDING SITE - varies depending on receptor type A) Monoamines: pocket in TM helices B) Peptide hormones: top of TM helices + extracellular loops + N-terminal chain C) Hormones: extracellular loops + N-terminal chain D) Glutamate: N-terminal chain Ligand B DCA
The alpha subunit of the G-protein is activated by... separating from the gamma and beta subunits. the G-protein changing conformation. binding to the calcium ions. replacing the GDP with GTP. replacing the GTP with GDP. The activated alpha subunit then binds to... the calcium ion channel. the calcium ions. the gamma and beta subunits. GDP GTP
As a result... the calcium channel opens and calcium ions leave the cell. the calcium channel opens and calcium ions enter the cell. the calcium channel closes. the calcium ions bind to calmodulin. the calcium ions bind to the ligand receptor site. The G-protein changes conformation when the GTP replaces the GDP on the alpha subunit. True False The combination of the calcium and the calmodulin produces the response of the cell to the ligand. True False
Bacteriorhodopsin & Rhodopsin Family • Rhodopsin = visual receptor • Many common receptors belong to this same family • Implications for drug selectivity depending on similarity (evolution) • Membrane bound receptors difficult to crystallise • X-Ray structure of bacteriorhodopsin solved - bacterial protein similar to rhodopsin • Bacteriorhodopsin structure used as ‘template’ for other receptors • Construct model receptors based on template and amino acid sequence • Leads to model binding sites for drug design • Crystal structures for rhodopsin and b2-adrenergic receptors now solved - better templates
Bacteriorhodopsin & Rhodopsin Family Common ancestor Endothelins Opsins, Rhodopsins Tachykinins Monoamines alpha beta H2 1 muscarinic H12 4 15 3 2A 2B 2C D1A D1B D5D4 D3 D2 3 2 1 Bradykinin, Angiotensin. Interleukin-8 Muscarinic Histamine -Adrenergic Dopaminergic b-Adrenergic Receptor types Receptor sub-types
• Receptor types and subtypes not equally distributed amongst tissues. • Target selectivity leads to tissue selectivity Heart muscle b1 adrenergic receptors Fat cells b3 adrenergic receptors Bronchial muscle 1& b2 adrenergic receptors GI-tract 1 2 & b2 adrenergic receptors RECEPTOR TYPES AND SUBTYPES
Enzyme linked receptors Tyrosine kinase - linked receptors • Bifunctional receptor / enzyme • Activated by hormones • Overexpression can result in cancer
• Protein serves dual role - receptor plus enzyme • Receptor binds messenger leading to an induced fit • Protein changes shape and opens active site • Reaction catalysed within cell • Overexpression related to several cancers closed messenger induced fit active site open intracellular reaction closed messenger Tyrosine kinase-linked receptors
N H2 C O2H Cell membrane Catalytic binding region (closed in resting state) Ligand binding region Extracellular N-terminal chain Intracellular C-terminal chain Hydrophilic transmembrane region (-helix) Tyrosine kinase-linked receptors
Reaction catalysed by tyrosine kinase N C O Protein Protein OH Tyrosine residue Tyrosine kinase Mg++ ATP ADP N C O Protein Protein O Phosphorylated tyrosine residue P
Epidermal growth factor receptor (EGF- R) Inactive EGF-R monomers Cell membrane Binding site for EGF EGF - protein hormone - bivalent ligand Active site of tyrosine kinase Induced fit opens tyrosine kinase active sites Ligand binding and dimerisation OH OHOH HO Phosphorylation ATP ADP OP OPOP PO EGF
• Active site on one half of dimer catalyses phosphorylation of Tyr residues on other half • Dimerisation of receptor is crucial • Phosphorylated regions act as binding sites for further proteins and enzymes • Results in activation of signalling proteins and enzymes • Message carried into cell Epidermal growth factor receptor (EGF- R)
Insulin receptor (tetrameric complex) Insulin Cell membrane Insulin binding site Kinase active site OP Phosphorylation ATP ADP OP OP PO Kinase active site opened by induced fit OH OHOH HO
Growth hormone receptor Tetrameric complex constructed in presence of growth hormone Growth hormone binding site Kinase active site Kinase active site opened by induced fit GH OH OH OH HO kinases GH receptors (no kinase activity) GH binding & dimerisation OP OPOP PO ATP ADP Activation and phosphorylation OH Binding of kinases OHOH HO
Intracellular receptors •Chemical messengers must cross cell membrane • Chemical messengers must be hydrophobic • Example-steroids and steroid receptors Zinc Zinc fingers contain Cys residues (SH) Allow S-Zn interactions CO2H H2N DNA binding region (‘zinc fingers’) Steroid binding region
Cell membrane Intracellular receptor Mechanism 4. Binds co-activator protein 1. Messenger crosses membrane 2. Binds to receptor 3. Receptor dimerisation 5. Complex binds to DNA 6. Transcription switched on or off 7. Protein synthesis activated or inhibited Messenger Receptor Receptor-ligand complex Dimerisation Co-activator protein DNA
Oestrogen receptor Oestradiol H12 Oestrogen receptor Binding site AF-2 regions Dimerisation & exposure of AF-2 regions Coactivator Nuclear transcription factor Coactivator DNA Transcription Intracellular receptors
Cyclic nucleotide Known binding proteins Pathway/Biological association cAMP 1.protein kinase A 2.cyclic nucleotide-gated ion channels 3.Epac 4.Catabolite Activator Protein (CAP) 1.smooth muscle relaxation 2.photo/olfactory receptors 3.glucagon production in pancreatic beta cells 4.lacoperon regulation in E. coli cGMP 1.cGMP-dependent protein kinase (PKG) 2.cyclic nucleotide-gated ion channels 1.smooth muscle relaxation 2.photo/olfactory receptors cCMP 1.cGMP kinase I 2.protein kinase A 1.smooth muscle relaxation
A simple intracellular signaling pathway activated by an extracellular signal molecule
Signaling through G-protein-coupled cell-surface receptors (GPCRs) and small intracellular mediators
Trimeric G proteins disassemble to relay signals from G-protein-linked receptors
Activation of a G protein by an activated GPCR
Some G-proteins regulate the production of cyclic AMP A nerve cell in culture responding to the neurotransmitter serotonin, which acts through a GPCR to cause a rapid rise in the intracellular concentration of cyclic AMP
The synthesis & degradation of cyclic AMP Many extracellular signals work by increasing cAMP concentration, and they do so by increasing the activity of adenyl cyclase rather than decreasing the activity of phosphodiesterase. All receptors that act via cAMP are coupled to a stimulatory G protein (Gs), which activates adenyl cyclase.
Cyclic-AMP-dependent protein kinase (PKA) mediates most of the effects of cyclic AMP Mammalian cells have at least two types of PKAs: • type I is mainly in the cytosol, • whereas type II is bound via its regulatory subunit and special anchoring proteins to the plasma membrane, nuclear membrane, mitochondrial outer membrane, and microtubules.
• Cyclic AMP induced responses could be rapid or slow. • In skeletal muscle cells, PKA induces a rapid response by phosphorylating enzymes involved in glycogen metabolism. • In an example of a slow response, cAMP activates transcription of a gene for a hormone, such as somatostatin *CREB: cAMP-response element-binding protein
Some G proteins activate the inositol phospholipid signaling pathway by activating phospholipase C-b The effects of IP3 can be mimicked by a Ca2+ ionophore (A23187 or ionomycin and the effects of diacylglycerol can be mimicked by phorbol esters
The hydrolysis of PI(4,5)P2 by phospholipase C-b
Ca2+ functions as a ubiquitous intracellular messenger Three main types of Ca2+ channels that mediate Ca2+ signaling: 1. Voltage dependent Ca2+ channels in the plasma membrane 2. IP3-gated Ca2+-release channels 3. Ryanodine receptors
The concentration of Ca2+ in the cytosol is kept low in resting cells by several mechanisms
Ca2+/ Calmodulin-dependent protein kinases (CaM-kinases) mediate many of the actions of Ca2+ in animal cells The structure of Ca2+/ Calmodulin
The stepwise activation of CaM-kinase II
BCDD
GABA A receptor  It is an ionotropic receptor and ligand-gated ion channel.  Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.  Upon activation, the GABA A receptor selectively conducts Cl− through its pore.  Cl- will flow out of the cell if the internal voltage is less than resting potential and Cl- will flow in if it is more than resting potential (i.e. -75 mV).  This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring.  The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).
GABA A receptor  The active site of the GABAA receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline.  The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly.  These allosteric sites are the targets of various drugs  benzodiazepines,  nonbenzodiazepines,  neuroactive steroids,  barbiturates,  alcohol (ethanol),  inhaled anaesthetics, and  Picrotoxin
GABA A receptor  GABAA receptors occur in all organisms that have a nervous system.  To a limited extent the receptors can be found in non-neuronal tissues.  Due to their wide distribution within the nervous system of mammals they play a role in virtually all brain functions.
GABA A STRUCTURE  The much sought structure of a GABAA receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABAA receptor.  The majority of GABAA receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site.  This was finally elucidated in 2018 by the publication of a high resolution cryo-EM structure of a human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil.
 GABAA receptors are pentameric transmembrane receptors which consist of five subunits arranged around a central pore.  Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly.  Some isoforms may be found extrasynaptically.  The ligand GABA is the endogenous compound that causes this receptor to open; once bound to GABA, the protein receptor changes conformation within the membrane, opening the pore in order to allow chloride anions (Cl−) to pass down an electrochemical gradient. GABA A STRUCTURE
GABA A STRUCTURE  the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential,  Hence activation of GABAA receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential.  The net effect is typically inhibitory, reducing the activity of the neuron.  However, depolarizing responses have been found to occur in response to GABA in immature neurons due to a modified Cl- gradient.  These depolarization events have shown to be key in neuronal development.  In the mature neuron, the GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).  The endogenous ligand that binds to the benzodiazepine site is inosine.
GABA A Function  The molecular target of the benzodiazepine class of tranquilizer drugs.  Bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABAA receptors.  While the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABAA receptors (α4- or α6- subunit containing) which are insensitive to classical 1,4- benzodiazepines,[10] but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and alcohol.
GABA A Function  In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds.  Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane.  This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.[citation needed]  Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity.  For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.[12]  Anticonvulsant effects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2- selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.
GABA A Function  In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.[citation needed]  Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.[12] Anticonvulsant effects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.  The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor, and also produces different effects on binding,[13] with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound.[14] Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.  Also note that some GABAA agonists such as muscimol and gaboxadol do bind to the same site on the GABAA receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.[citation needed]
Glucagon-like peptide-1 receptor
GLP1R  The GLP1R is a receptor protein.  Binds glucagon-like peptide-1 (GLP1) and glucagon as its natural endogenous agonists.  Found on beta cells of the pancreas and on neurons of the brain.  It is involved in the control of blood sugar level by enhancing insulin secretion.  In humans it is synthesized by the gene GLP1R, which is present on chromosome 6.  It is a member of the glucagon receptor family of G protein- coupled receptors.
GLP1R Structure  The GLP-1 receptor sequence contains a large hydrophilic extracellular domain and seven hydrophobic transmembrane domains.  The GLP-1 receptor protein has three potential N-linked glycosylation sites, and glycosylation may modulate receptor function.  GLP1R is composed of two domains:  one extracellular (ECD) that binds the C-terminal helix of GLP-1 and  One transmembrane (TMD) domain that binds the N- terminal region of GLP-1.  In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.
GLP1R Function  Activated GLP1R stimulates the adenylyl cyclase pathway which results in increased insulin synthesis and release of insulin.  Consequently, GLP1R has been a target for developing drugs usually referred to as GLP1R agonists to treat diabetes mellitus.  Exendin-4 is one of the peptides used therapeutically to treat diabetes, and its biological binding mode to the GLP-1R has been demonstrated using genetically engineered amino acids.  GLP1R is also expressed in the brain where it is involved in the control of appetite.  Furthermore, mice that over express GLP1R display improved memory and learning.  Stretch responsive vagal neurons in the stomach and intestines also express GLP1R.  GLP1R neurons particularly and densely innervate stomach muscle and can communicate with additional organ systems changing breathing and heart rate due to activation.
Signal Transduction Pathway GLP1R  The GLP-1 receptor is functionally coupled to AC via Gs.  Through activation of AC, cAMP is formed and activates PKA.  Ligand stimulation of the receptor also increases the cytoplasmic concentration of Ca2+;  this is thought to be executed both through Na+- dependent uptake of extracellular Ca2+ and through release of Ca2+ from intracellular Ca2+ stores.  The increased cytosolic Ca2+ in conjunction with the activated PKA stimulates the translocation and exocytosis of insulin-containing secretory granules
Agonists & Antagonists Agonists  Exendin-4 or Exenatide, was the first FDA approved “incretin mimetic”;  Liraglutide, a long-acting GLP-1 receptor agonist, was 2nd .  Other agonists are  CJC-1131, a GLP-1 analog engineered for covalent coupling to albumin;  Albiglutide, a recombinant human albumin-GLP-1 protein;  ZP10, an exendin-4 derivative;  Taspoglutide  Dulaglutide Antagonists  Exendin (9–39) and T-0632, a small non-peptide ligand, are antagonists.
Serotonin
Serotonin deficit
Glucocorticoid receptor (GR, or GCR)  The GR is also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1)  Binds to cortisol and glucocorticoids.  The GR is expressed in almost every cell in the body and regulates genes controlling the development, metabolism, and immune response.

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Receptors Types and details

  • 1.
  • 2.
    The role ofthe receptor • Globular proteins • Located mostly in the cell membrane • Receive messages from chemical messengers coming from other cells (CNS) • Transmit a message into the cell leading to a cellular effect • Different receptors specific for different chemical messengers • Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers
  • 3.
    The Role ofthe receptor Cell Nerve Messenger Signal Receptor Nerve Nucleus Cell Response
  • 4.
    The Role ofthe receptor  Neurotransmitters: Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells  Hormones: Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body  Note: Chemical messengers ‘switch on’ receptors without undergoing a reaction
  • 5.
    The role ofthe receptor •Receptors contain a binding site (hollow or cleft on the receptor surface) that is recognised by the chemical messenger •Binding of the messenger involves intermolecular bonds •Binding results in an induced fit of the receptor protein •Change in receptor shape results in a ‘domino’ effect •Domino effect is known as signal transduction, leading to a chemical signal being received inside the cell •Chemical messenger does not enter the cell. It departs the receptor unchanged and is not permanently bound
  • 6.
    The Binding Site Cell Membrane Cell Receptor Messenger message Inducedfit Cell Receptor Messenger Message Cell Messenger Receptor
  • 7.
    The Binding Site •A hydrophobic hollow or cleft on the receptor surface - equivalent to the active site of an enzyme • Accepts and binds a chemical messenger • Contains amino acids which bind the messenger • No reaction or catalysis takes place ENZYME Binding site
  • 8.
    The Binding Site •Binding site is nearly the correct shape for the messenger • Binding alters the shape of the receptor (induced fit) • Altered receptor shape leads to further effects - signal transduction Messenge r Induced fit M
  • 9.
    How does theBinding Site Change Shape?  Before –  Intermolecular bonds not optimum length for maximum binding strength  After –  Intermolecular bond lengths optimised Phe Ser O H Asp CO2 Induced Fit Phe Ser O H Asp CO2
  • 10.
    Induced Fit • Bindinginteractions must be strong enough to hold the messenger sufficiently long for signal transduction to take place • Interactions must be weak enough to allow the messenger to depart • Implies a fine balance • Designing molecules with stronger binding interactions results in drugs that block the binding site - antagonists M M ER R M ER Signal transduction
  • 11.
    Main Types ofReceptors • ION CHANNEL RECEPTORS • G-PROTEIN-COUPLED RECEPTORS • KINASE-LINKED RECEPTORS • INTRACELLULAR RECEPTORS
  • 12.
    Ion Channel Receptors •Receptor protein is part of an ion channel protein complex • Receptor binds a messenger leading to an induced fit • Ion channel is opened or closed • Ion channels are specific for specific ions (Na+, Ca2+, Cl-, K+) • Ions flow across cell membrane down concentration gradient • Polarises or depolarises nerve membranes • Activates or deactivates enzyme catalysed reactions within cell
  • 13.
    Ion Channel Receptors Hydrophilic tunnel Cell membrane Inducedfit and opening of ion channel ION CHANNEL (open) Cell Cell membrane MESSENGER Ion channel Ion channel Cell membrane RECEPTOR BINDING SITE Cell Lock Gate Ion channel Ion channel Cell membrane Cell membrane MESSENGER
  • 14.
    Ion Channel Receptors TransmembraneProteins TM2 of each protein subunit ‘lines’ the central pore Protein subunits TM4 TM4TM4 TM3 TM3 TM3 TM3 TM3 TM2 TM2 TM2TM2 TM2 TM1 TM1 TM1 TM1 TM1 TM4 TM4
  • 15.
    Gating Five glycoprotein subunits traversingcell membrane MessengerReceptor Induced fit ‘Gating’ (ion channel opens) Binding site Cell membrane Cell membrane
  • 16.
    gating • Chemical messengerbinds to receptor binding site • Induced fit results in further conformational changes • TM2 segments rotate to open central pore Closed Transverse view TM2 TM2 TM2 TM2 TM2 Cell membrane TM2 TM2 Open Transverse view TM2 TM2 TM2 TM2 TM2
  • 17.
    Gating • Fast responsemeasured in msec • Ideal for transmission between nerves • Binding of messenger leads directly to ion flows across cell membrane • Ion flow = secondary effect (signal transduction) • Ion concentration within cell alters • Leads to variation in cell chemistry
  • 18.
    • Receptor bindsa messenger leading to an induced fit • Opens a binding site for a signal protein (G-protein) • G-protein binds, is destabilised then split messenger G-protein split G-PROTEIN-COUPLED RECEPTORS induced fit closed open
  • 19.
    • G-protein subunitactivates membrane bound enzyme • Binds to allosteric binding site • Induced fit results in opening of active site • Intracellular reaction catalysed Intracellular reaction active site (closed) active site (open) Enzyme Enzyme G-PROTEIN-COUPLED RECEPTORS
  • 20.
    Transmembrane helix C -Terminal chain G-Protein bindingregion Variable intracellular loop Extracellular loops Intracellular loops N -Terminal chain HO2C NH2 VII VI V IV III II IMembrane G-PROTEIN-COUPLED RECEPTORS
  • 21.
    LIGAND BINDING SITE- varies depending on receptor type A) Monoamines: pocket in TM helices B) Peptide hormones: top of TM helices + extracellular loops + N-terminal chain C) Hormones: extracellular loops + N-terminal chain D) Glutamate: N-terminal chain Ligand B DCA
  • 22.
    The alpha subunitof the G-protein is activated by... separating from the gamma and beta subunits. the G-protein changing conformation. binding to the calcium ions. replacing the GDP with GTP. replacing the GTP with GDP. The activated alpha subunit then binds to... the calcium ion channel. the calcium ions. the gamma and beta subunits. GDP GTP
  • 23.
    As a result... thecalcium channel opens and calcium ions leave the cell. the calcium channel opens and calcium ions enter the cell. the calcium channel closes. the calcium ions bind to calmodulin. the calcium ions bind to the ligand receptor site. The G-protein changes conformation when the GTP replaces the GDP on the alpha subunit. True False The combination of the calcium and the calmodulin produces the response of the cell to the ligand. True False
  • 24.
    Bacteriorhodopsin & RhodopsinFamily • Rhodopsin = visual receptor • Many common receptors belong to this same family • Implications for drug selectivity depending on similarity (evolution) • Membrane bound receptors difficult to crystallise • X-Ray structure of bacteriorhodopsin solved - bacterial protein similar to rhodopsin • Bacteriorhodopsin structure used as ‘template’ for other receptors • Construct model receptors based on template and amino acid sequence • Leads to model binding sites for drug design • Crystal structures for rhodopsin and b2-adrenergic receptors now solved - better templates
  • 25.
    Bacteriorhodopsin & RhodopsinFamily Common ancestor Endothelins Opsins, Rhodopsins Tachykinins Monoamines alpha beta H2 1 muscarinic H12 4 15 3 2A 2B 2C D1A D1B D5D4 D3 D2 3 2 1 Bradykinin, Angiotensin. Interleukin-8 Muscarinic Histamine -Adrenergic Dopaminergic b-Adrenergic Receptor types Receptor sub-types
  • 26.
    • Receptor typesand subtypes not equally distributed amongst tissues. • Target selectivity leads to tissue selectivity Heart muscle b1 adrenergic receptors Fat cells b3 adrenergic receptors Bronchial muscle 1& b2 adrenergic receptors GI-tract 1 2 & b2 adrenergic receptors RECEPTOR TYPES AND SUBTYPES
  • 27.
    Enzyme linked receptors Tyrosinekinase - linked receptors • Bifunctional receptor / enzyme • Activated by hormones • Overexpression can result in cancer
  • 28.
    • Protein servesdual role - receptor plus enzyme • Receptor binds messenger leading to an induced fit • Protein changes shape and opens active site • Reaction catalysed within cell • Overexpression related to several cancers closed messenger induced fit active site open intracellular reaction closed messenger Tyrosine kinase-linked receptors
  • 29.
    N H2 C O2H Cellmembrane Catalytic binding region (closed in resting state) Ligand binding region Extracellular N-terminal chain Intracellular C-terminal chain Hydrophilic transmembrane region (-helix) Tyrosine kinase-linked receptors
  • 30.
    Reaction catalysed bytyrosine kinase N C O Protein Protein OH Tyrosine residue Tyrosine kinase Mg++ ATP ADP N C O Protein Protein O Phosphorylated tyrosine residue P
  • 31.
    Epidermal growth factorreceptor (EGF- R) Inactive EGF-R monomers Cell membrane Binding site for EGF EGF - protein hormone - bivalent ligand Active site of tyrosine kinase Induced fit opens tyrosine kinase active sites Ligand binding and dimerisation OH OHOH HO Phosphorylation ATP ADP OP OPOP PO EGF
  • 32.
    • Active siteon one half of dimer catalyses phosphorylation of Tyr residues on other half • Dimerisation of receptor is crucial • Phosphorylated regions act as binding sites for further proteins and enzymes • Results in activation of signalling proteins and enzymes • Message carried into cell Epidermal growth factor receptor (EGF- R)
  • 33.
    Insulin receptor (tetramericcomplex) Insulin Cell membrane Insulin binding site Kinase active site OP Phosphorylation ATP ADP OP OP PO Kinase active site opened by induced fit OH OHOH HO
  • 34.
    Growth hormone receptor Tetramericcomplex constructed in presence of growth hormone Growth hormone binding site Kinase active site Kinase active site opened by induced fit GH OH OH OH HO kinases GH receptors (no kinase activity) GH binding & dimerisation OP OPOP PO ATP ADP Activation and phosphorylation OH Binding of kinases OHOH HO
  • 35.
    Intracellular receptors •Chemical messengersmust cross cell membrane • Chemical messengers must be hydrophobic • Example-steroids and steroid receptors Zinc Zinc fingers contain Cys residues (SH) Allow S-Zn interactions CO2H H2N DNA binding region (‘zinc fingers’) Steroid binding region
  • 36.
    Cell membrane Intracellular receptor Mechanism 4.Binds co-activator protein 1. Messenger crosses membrane 2. Binds to receptor 3. Receptor dimerisation 5. Complex binds to DNA 6. Transcription switched on or off 7. Protein synthesis activated or inhibited Messenger Receptor Receptor-ligand complex Dimerisation Co-activator protein DNA
  • 37.
    Oestrogen receptor Oestradiol H12 Oestrogen receptor Binding site AF-2 regions Dimerisation& exposure of AF-2 regions Coactivator Nuclear transcription factor Coactivator DNA Transcription Intracellular receptors
  • 38.
    Cyclic nucleotide Known binding proteins Pathway/Biological association cAMP 1.proteinkinase A 2.cyclic nucleotide-gated ion channels 3.Epac 4.Catabolite Activator Protein (CAP) 1.smooth muscle relaxation 2.photo/olfactory receptors 3.glucagon production in pancreatic beta cells 4.lacoperon regulation in E. coli cGMP 1.cGMP-dependent protein kinase (PKG) 2.cyclic nucleotide-gated ion channels 1.smooth muscle relaxation 2.photo/olfactory receptors cCMP 1.cGMP kinase I 2.protein kinase A 1.smooth muscle relaxation
  • 39.
    A simple intracellularsignaling pathway activated by an extracellular signal molecule
  • 41.
    Signaling through G-protein-coupledcell-surface receptors (GPCRs) and small intracellular mediators
  • 42.
    Trimeric G proteinsdisassemble to relay signals from G-protein-linked receptors
  • 43.
    Activation of aG protein by an activated GPCR
  • 44.
    Some G-proteins regulatethe production of cyclic AMP A nerve cell in culture responding to the neurotransmitter serotonin, which acts through a GPCR to cause a rapid rise in the intracellular concentration of cyclic AMP
  • 45.
    The synthesis &degradation of cyclic AMP Many extracellular signals work by increasing cAMP concentration, and they do so by increasing the activity of adenyl cyclase rather than decreasing the activity of phosphodiesterase. All receptors that act via cAMP are coupled to a stimulatory G protein (Gs), which activates adenyl cyclase.
  • 46.
    Cyclic-AMP-dependent protein kinase(PKA) mediates most of the effects of cyclic AMP Mammalian cells have at least two types of PKAs: • type I is mainly in the cytosol, • whereas type II is bound via its regulatory subunit and special anchoring proteins to the plasma membrane, nuclear membrane, mitochondrial outer membrane, and microtubules.
  • 47.
    • Cyclic AMPinduced responses could be rapid or slow. • In skeletal muscle cells, PKA induces a rapid response by phosphorylating enzymes involved in glycogen metabolism. • In an example of a slow response, cAMP activates transcription of a gene for a hormone, such as somatostatin *CREB: cAMP-response element-binding protein
  • 48.
    Some G proteinsactivate the inositol phospholipid signaling pathway by activating phospholipase C-b The effects of IP3 can be mimicked by a Ca2+ ionophore (A23187 or ionomycin and the effects of diacylglycerol can be mimicked by phorbol esters
  • 49.
    The hydrolysis ofPI(4,5)P2 by phospholipase C-b
  • 50.
    Ca2+ functions asa ubiquitous intracellular messenger Three main types of Ca2+ channels that mediate Ca2+ signaling: 1. Voltage dependent Ca2+ channels in the plasma membrane 2. IP3-gated Ca2+-release channels 3. Ryanodine receptors
  • 51.
    The concentration ofCa2+ in the cytosol is kept low in resting cells by several mechanisms
  • 53.
    Ca2+/ Calmodulin-dependent proteinkinases (CaM-kinases) mediate many of the actions of Ca2+ in animal cells The structure of Ca2+/ Calmodulin
  • 54.
    The stepwise activationof CaM-kinase II
  • 55.
  • 56.
    GABA A receptor It is an ionotropic receptor and ligand-gated ion channel.  Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.  Upon activation, the GABA A receptor selectively conducts Cl− through its pore.  Cl- will flow out of the cell if the internal voltage is less than resting potential and Cl- will flow in if it is more than resting potential (i.e. -75 mV).  This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring.  The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).
  • 57.
    GABA A receptor The active site of the GABAA receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline.  The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly.  These allosteric sites are the targets of various drugs  benzodiazepines,  nonbenzodiazepines,  neuroactive steroids,  barbiturates,  alcohol (ethanol),  inhaled anaesthetics, and  Picrotoxin
  • 58.
    GABA A receptor GABAA receptors occur in all organisms that have a nervous system.  To a limited extent the receptors can be found in non-neuronal tissues.  Due to their wide distribution within the nervous system of mammals they play a role in virtually all brain functions.
  • 59.
    GABA A STRUCTURE The much sought structure of a GABAA receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABAA receptor.  The majority of GABAA receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site.  This was finally elucidated in 2018 by the publication of a high resolution cryo-EM structure of a human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil.
  • 60.
     GABAA receptorsare pentameric transmembrane receptors which consist of five subunits arranged around a central pore.  Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly.  Some isoforms may be found extrasynaptically.  The ligand GABA is the endogenous compound that causes this receptor to open; once bound to GABA, the protein receptor changes conformation within the membrane, opening the pore in order to allow chloride anions (Cl−) to pass down an electrochemical gradient. GABA A STRUCTURE
  • 61.
    GABA A STRUCTURE the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential,  Hence activation of GABAA receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential.  The net effect is typically inhibitory, reducing the activity of the neuron.  However, depolarizing responses have been found to occur in response to GABA in immature neurons due to a modified Cl- gradient.  These depolarization events have shown to be key in neuronal development.  In the mature neuron, the GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).  The endogenous ligand that binds to the benzodiazepine site is inosine.
  • 62.
    GABA A Function The molecular target of the benzodiazepine class of tranquilizer drugs.  Bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABAA receptors.  While the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABAA receptors (α4- or α6- subunit containing) which are insensitive to classical 1,4- benzodiazepines,[10] but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and alcohol.
  • 63.
    GABA A Function In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds.  Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane.  This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.[citation needed]  Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity.  For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.[12]  Anticonvulsant effects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2- selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.
  • 64.
    GABA A Function In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.[citation needed]  Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.[12] Anticonvulsant effects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.  The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor, and also produces different effects on binding,[13] with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound.[14] Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.  Also note that some GABAA agonists such as muscimol and gaboxadol do bind to the same site on the GABAA receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.[citation needed]
  • 65.
  • 66.
    GLP1R  The GLP1Ris a receptor protein.  Binds glucagon-like peptide-1 (GLP1) and glucagon as its natural endogenous agonists.  Found on beta cells of the pancreas and on neurons of the brain.  It is involved in the control of blood sugar level by enhancing insulin secretion.  In humans it is synthesized by the gene GLP1R, which is present on chromosome 6.  It is a member of the glucagon receptor family of G protein- coupled receptors.
  • 67.
    GLP1R Structure  TheGLP-1 receptor sequence contains a large hydrophilic extracellular domain and seven hydrophobic transmembrane domains.  The GLP-1 receptor protein has three potential N-linked glycosylation sites, and glycosylation may modulate receptor function.  GLP1R is composed of two domains:  one extracellular (ECD) that binds the C-terminal helix of GLP-1 and  One transmembrane (TMD) domain that binds the N- terminal region of GLP-1.  In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.
  • 68.
    GLP1R Function  ActivatedGLP1R stimulates the adenylyl cyclase pathway which results in increased insulin synthesis and release of insulin.  Consequently, GLP1R has been a target for developing drugs usually referred to as GLP1R agonists to treat diabetes mellitus.  Exendin-4 is one of the peptides used therapeutically to treat diabetes, and its biological binding mode to the GLP-1R has been demonstrated using genetically engineered amino acids.  GLP1R is also expressed in the brain where it is involved in the control of appetite.  Furthermore, mice that over express GLP1R display improved memory and learning.  Stretch responsive vagal neurons in the stomach and intestines also express GLP1R.  GLP1R neurons particularly and densely innervate stomach muscle and can communicate with additional organ systems changing breathing and heart rate due to activation.
  • 69.
    Signal Transduction Pathway GLP1R The GLP-1 receptor is functionally coupled to AC via Gs.  Through activation of AC, cAMP is formed and activates PKA.  Ligand stimulation of the receptor also increases the cytoplasmic concentration of Ca2+;  this is thought to be executed both through Na+- dependent uptake of extracellular Ca2+ and through release of Ca2+ from intracellular Ca2+ stores.  The increased cytosolic Ca2+ in conjunction with the activated PKA stimulates the translocation and exocytosis of insulin-containing secretory granules
  • 70.
    Agonists & Antagonists Agonists Exendin-4 or Exenatide, was the first FDA approved “incretin mimetic”;  Liraglutide, a long-acting GLP-1 receptor agonist, was 2nd .  Other agonists are  CJC-1131, a GLP-1 analog engineered for covalent coupling to albumin;  Albiglutide, a recombinant human albumin-GLP-1 protein;  ZP10, an exendin-4 derivative;  Taspoglutide  Dulaglutide Antagonists  Exendin (9–39) and T-0632, a small non-peptide ligand, are antagonists.
  • 71.
  • 73.
  • 77.
    Glucocorticoid receptor (GR,or GCR)  The GR is also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1)  Binds to cortisol and glucocorticoids.  The GR is expressed in almost every cell in the body and regulates genes controlling the development, metabolism, and immune response.