2. LIGAND-GATED ION CHANNELS
• Ionotropic receptors.
• Nervous system
-excitatory ( Ach , glutamate)
- inhibitory( glycine or GABA)
• Fast synaptic transmission
• E.g. - Nicotinic Acetylcholine receptor at NM junction.
- GABAA receptor
3. Molecular structure
• Commonest- heteromeric assemblies of 4 or 5 subunits
e.g. -Pentameric – nAchr
-Tetrameric –NMDA
• Transmembrane helices arranged around a central aqueous
channel.
18. Receptor serine/threonine kinases-
• Analogous to the receptor tyrosine kinases
• Phosphorylation of serine and/or threonine
• The activated receptor , phosphorylates SMAD
• e.g. TGF-β
19. MECHANISM OF ACTION
Agonist binding
Dimerization of receptor
Phosphorylation of kinase
Phosphorylation of SMAD
Gene transcription
20. CLINICAL SIGNIFICANCE
Under trial (phase 3)
SELUMETINIB -differentiated thyroid cancer
-K-Ras protein mutated non-small cell lung cancer.
21. Toll-Like Receptors-
• Signaling related to the innate immune system.
• Highly expressed in hematopoietic cells.
• Ligands - pathogen products (lipids, peptidoglycans, lipopeptides)
and viruses.
• Activation of these receptors produces an inflammatory responses
22. MECHANISM OF ACTION
Ligand-induced dimerization
MAL/MyD88 recruitment ( IRAKs autophosphorylation)
TRAF6 activation
Interaction with TAB1 and TAK1
Phosphorylation of the NF-κB Transcription
28. Nuclear receptors-
• NRs can directly interact with DNA - “ ligand activated transcription
factors”.
• These transduce signals by modifying gene transcription.
• E.g. glucocorticoids, mineralocorticoids, Vit D and A
30. TYPES OF NUCLEAR RECEPTOR
CLASS 1 CLASS 2
Location Cytosolic Nuclear
Ligand binding Homodimers Heterodimers often with RXR
Mechanism of action Translocation to nucleus.
Binding to HREs
Complexed with co-repressors,
which are displaced following
ligand binding, allowing the
binding of trans activators
E.G. Estrogen ( Er α)
Glucocorticoid( GRα )
Retinoid X (RXR α,β,γ)
Thyroid hormone (TR α,β )
Ligand binding and channel opening occur on a millisecond timescale. Major ligand-gated channels in the nervous system are those that respond to excitatory neurotransmitters such as ACh or glutamate and inhibitory neurotransmitters such as glycine or GABA . Ligand (Latin: ligare—to bind) Any molecule which attaches selectively to particular receptors or sites
There are several structural families, the commonest being heteromeric assemblies of four or five subunits, with transmembrane helices arranged around a central aqueous channel. nAChR, nicotinic acetylcholine receptor, NMDA, N-methyl-D-aspartic acid receptor
consists of a pentameric assembly of different subunits, of which there are four types, termed α, β, γ and δ, each of molecular weight (Mr) 40–58 kDa
They are activated by a wide variety of protein mediators, including growth factors and cytokines and hormones such as insulin and leptin. They have large extracellular ligand binding domain connected through a single transmembrane helical peptide chain to an intracellular subunit having enzymatic property in the cytosolic phase.
1-they incorporate tyrosine kinase in their intracellular domain. Cytokine receptors. These receptors (Fig. 3.17B) lack intrinsic enzyme activity. When occupied, they activate various tyrosine kinases, such as Jak (the Janus kinase).
With the exception of the insulin receptor, which has α and β chains (see Chapter 47), these macromolecules consist of single polypeptide chains with large, cysteine-rich extracellular domains, short transmembrane domains, and an intracellular region containing one or two protein tyrosine kinase domains. Activation of growth factor receptors leads to cell survival, cell proliferation, and differentiation. Activation of the ephrin receptors leads to neuronal angiogenesis, axonal migration, and guidance
The first step following agonist binding is dimerisation, which leads to autophosphorylation of the intracellular domain of each receptor. SH2-domain proteins then bind to the phosphorylated receptor and are themselves phosphorylated.
Ras –GTP ase family RAF proto-oncogene serine/threonine-protein kinase Growth factor receptor-bound protein 2
BCR-ABL is a constitutively activated tyrosine kinase that is associated with chronic myeloid leukemia
oral tyrosine kinase inhibitor that acts upon vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR
The intracellular domain binds a separate, intracellular tryosine kinase termed a Janus kinase (JAK). • JAKs phosphorylate other proteins termed signal transducers and activators of transcription (STATs).
Jak/Stat pathway (Fig. 3.17B) is involved in responses to many cytokines. Dimerisation of these receptors occurs when the cytokine binds, and this attracts a cytosolic tyrosine kinase unit (Jak) to associate with, and phosphorylate, the receptor dimer. Jaks belong to a family of proteins, different members having specificity for different cytokine receptors. Among the targets for phosphorylation by Jak are a family of transcription factors (Stats). These are SH2-domain proteins that bind to the phosphotyrosine groups on the receptor–Jak complex, and are themselves phosphorylated. Thus activated, Stat migrates to the nucleus and activates gene expression
analogous to the receptor tyrosine kinases except that they have a serine-threonine kinase domain in the cytoplasmic region of the protein
Gene regulatory protein smad
Transforming growth factor beta receptors
Samd proteins are transcription protiens
The orally administered drug has dual specificity for mitogen-activated protein kinase inhibitors
AstraZeneca plc
TLR DOMAIN- toll/interleukin-1 domain
Myeloid differentiation primary response 88 (MYD88
Myelin and lymphocyte protein is a protein that in humans is encoded by the MAL gene
Interleukin-1 receptor-associated kinase 1
TNF receptor associated factor (TRAF)
TGF-beta activated kinase 1 (MAP3K7) binding protein 1
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1
nuclear factor kappa-light-chain-enhancer of activated B cells
T-cell development, maturation, and proliferation.[4
B-type natriuretic peptide, a hormone secreted by the ventricles in response to volume overload, acts via a receptor guanylyl cyclase
Nesiritide (Natrecor) is the recombinant form of the 32 amino acid human B-type natriuretic peptide, which is normally produced by the ventricular myocardium. Nesiritide works to facilitate cardiovascular fluid homeostasis through counterregulation of the renin–angiotensin–aldosterone system, stimulating cyclic guanosine monophosphate, leading to smooth muscle cell relaxation.
Cyclic GMP signaling pathways. Formation of cGMP is regulated by cell surface receptors with intrinsic GC activity and by soluble forms of GC. The cell surface receptors respond to natriuretic peptides such as ANP with an increase in cGMP. sGC responds to NO generated from l-arginine by NOS. Cellular effects of cGMP are carried out by PKG and cGMP-regulated PDEs. In this diagram, NO is produced by a Ca2+/calmodulin–dependent NOS in an adjacent endothelial cell
protein kinase G phosphodiesterase enzyme
First cloned receptor –retinoid x receptor ( vitamin A derivative 9-cisretinoic acid )
AF1 - binds cell specific transcription factors Core domain - DNA recognition and binding Zinc finger – hormone response elements in gene
cysteine- (or cystine-/histidine-) rich loops in the amino acid chain that are held in a particular conformation by zinc ions
C-terminal domain- ligand binding domain
Hinge region – receptor dimerization
HRE – short sequence of DNA that is able to attach to a hormone receptor complex
transactivate or transrepress genes by binding to ‘positive’ or ‘negative’ HREs
Class II NRs are generally bound to co-repressor proteins
NRs almost always operate as heterodimers together with the retinoid X receptor (RXR).
