2. Molecules that relay signals from receptors on the cell surface
to target molecules inside the cell i.e. cytoplasm or nucleus
Relay the signals of hormones like epinephrine, growth factors
& others; causing some kind of change in the activity of the cell
The term was coined upon the discovery of these substances
in order to distinguish them from hormones & other molecules
that function outside the cell as “first messengers” in the
transmission of biological information
3. Earl Wilbur Sutherland Jr.
discovered second messengers
won the 1971 Nobel Prize in Medicine
He saw that epinephrine would
stimulate the liver to convert glycogen
to glucose in liver cells, but
epinephrine alone would not convert
glycogen to glucose
He found that epinephrine had to trigger a
second messenger, cyclic AMP for the liver to convert
glycogen to glucose
5. G- Proteins
Guanine nucleotide binding proteins which act as a Transducer
between a receptor & an effector
Discovered by Alfred Gilman & Martin Rodbell in 1990
Significance:
• Of the top 100 drugs,
26 directed at GPCRs
• 60 % act through GPCRs
• 40 % of prescriptions
• 3rd largest family of genes (865)
• Present in almost every organ system
7. Structure:
Embedded in the plasma membrane
7 transmembrane -helices
Rhodopsin was first of these
to have its structure confirmed by
X-ray crystallography
-Adrenergic
Receptor
PDB 2RH1
Lysozyme
insert
ligand
8. Binding Domains
Small molecular ligands
bind to sites within the
hydrophobic core formed by
transmembrane α helices
Protein and peptide agonists
bind to N terminus &
extracellular hydrophilic
loops joining the
transmembrane domain
G-proteins bind either to
second and third
cytoplasmic loop which is
largest or to carboxy terminus
9. Molecular Switch: On/Off
Heterotrimeric
α-subunit
β-subunit
γ-subunit
α subunit: specific recognition of
receptors & effectors;
GTP binding site
βƔ subunit: Membrane localisation by prenylation of Ɣ subunit
Coded by of genes:
α – 23, β-7, Ɣ-12
11. Receptors Couplers
Muscarinic Gi, Go, Gq
Dopamine D2 Gi, Go
β-adrenergic Gs, Gi
α2-adrenergic Gi, Gs, Go
GABA-B Gi, Go
5-HT Gi, Gq, Gs
12. G Protein Activation
Conformational change
in receptor
Transmitted from ligand
binding pocket to 2nd & 3rd
intracellular loop
α subunit exchange GDP
with GTP
Presence of GEF‟s
(Guanine exchange factors)
Release of GTP bound
α subunit & βƔ dimer
13. Inactivation
Activated α subunit is
inactivated by hydrolysis
of GTP to GDP by GAPs
(GTPase Activating
Proteins)
Rebinds to βƔ complex
Modulated by
Regulators of G
proteins Signaling (RGSs)
Acclerate hydrolysis of
GTP & potential drug
targets
14. Toxins
Cholera toxin catalyzes covalent modification of Gs
• ADP-ribose is transferred from NAD+ to an arginine residue
at the GTPase active site of Gs
• ADP-ribosylation prevents GTP hydrolysis by Gs
• The stimulatory G-protein is permanently activated.
Pertussis toxin catalyzes ADP-ribosylation at a cysteine residue
of the inhibitory Gi, making it incapable of exchanging GDP for
GTP
• The inhibitory pathway is blocked.
ADP-ribosylation is a general mechanism by which activity of
many proteins is regulated, in eukaryotes & prokaryotes.
15. Receptor Desensitization
Activated receptor is
phosphorylated via a
G-protein Receptor Kinase
Binds to a protein arrestin
promotes removal of the
receptor from the membrane by
clathrin-mediated endocytosis
May also bind a cytosolic
Phosphodiesterase, bringing
this enzyme close to where
cAMP is being produced,
contributing to signal turnoff
17. Adenyl Cyclase
9 membrane bound, 1 soluble isoform (AC1-10)
120kDa
Basal enzymatic activity modulated by
GTP liganded α subunit Gs & Gi
Other regulatory interactions: βƔ subunits, Ca2+, protein
kinase & diterpene forskolin
Dephophorylation of ATP by removal of 2 phosphate
molecules→ cAMP
18. cAMP has following major targets:
1. cAMP dependent Protein Kinase A (PKA)
2. cAMP regulated Guanine nucleotide exchange factors
termed EPACs (Exchange Proteins Activated by cAMP)
3. CREB (cAMP responsive element binding protein)
19. Protein Phosphorylation→ most common form of post-
translational modification in nature
Protein function altered by addition of a negatively charged
phosphate group to a Ser, Thr or Tyr residue by Protein Kinase:
• Binding properties
• Enzymatic activity if a catalytic protein
Protein phosphatase catalyzes removal of the Pi by hydrolysis
Protein OH + ATP Protein O P
O
O
O
+ ADP
Pi H2O
Protein Kinase
Protein Phosphatase
20. 1. Protein Kinase A
Holoenzyme: 2 Regulatory(R) & 2 Catalytic(C) subunits
Heterotetramer complex R2C2
↓ cAMP, R inhibits C→ inactive
↑ cAMP→ 4 cAMP mols bind to R2C2, 2 to each R→ lowers
affinity to C → Activation
21. Active C subunits→
Phosphorylate serine/threonine residues on proteins
As protein expression varies from cell type to cell type,
proteins that are available for phosphorylation will depend upon
the cell type
Phosphorylation of ion channels→ Regulation
(Ca2+ activated K+ channel activation & Na+/K+ ATPase)
Inhibition of Myosin Light Chain Kinase
22. Cell Type Stimulators Inhibitors Effects
Hepatocyte Epinephrine(β),
Glucagon
Produce glucose:
stimulate glycogenolysis,
inhibit glycogenesis,
stimulate gluconeogenesis,
inhibit glycolysis.
Skeletal -
Myocyte
Epinephrine(β) Produce glucose:
stimulate glycogenolysis,
inhibit glycogenesis,
stimulate glycolysis
Cardio-
myocyte
Norepinephrine
(β)
Sequester Ca2+ in
sarcoplasmic reticulum,
Phosphorylates
phospholamban
Actions of Protein kinase A
24. 2. cAMP Response
Element-Binding
(CREB)
Cellular transcription factor
Genes: c-fos, the neurotrophin
BDNF, tyrosine hydroxylase &
many neuropeptides
Neuronal plasticity & long-term
memory formation
Development & progression of
Huntington‟s Chorea
25. 3. Exchange Proteins Activated
by cAMP (EPAC)
cAMP Regulated Guanine Nucleotide
Exchange Factors
Bind to GDP liganded GTPase,
exchange of GDP for GTP
Activation of PKC
Cell differentiation/proliferation, cytoskeletal
organization, vesicular trafficking & nuclear transport
Additional effector system
Potential target for cancer therapy
32. Unlike cAMP, cGMP has established signaling roles in only
few cell types
Signaling pathways that regulate synthesis include:
1. Nitric Oxide
2. Hormonal Regulation (ANP/BNP/CNP)
33. 1. Nitric Oxide
Nitric oxide: diatomic free radical gas
Lipid soluble
Very small→ easy passage between cell membranes
Short lived, degraded or reacted within a few seconds
Synthesis:
Synthesized from L-arginine catalyzed by
reaction of NO-synthase
to form NO and L-citrulline
34. Nitric Oxide Synthase (NOS) exists as 4 isoforms
neuronal type I isoform (nNOS)
inducible type II isoform (iNOS)
endothelial type III isoform (eNOS)
mitochondrial isoform (mtNOS)
36. Control exerted in following ways:
Endothelium-dependent agonists (Ach, bradykinin, substance P)
↑ cytoplasmic concentration of Ca2+ ↑calcium-calmodulin
eNOS or nNOS activation
Shear stress in resistance vessels→ Sensed by
mechanoreceptors→ Transduced via a serine threonine protein kinase
called Protein kinase B/ Akt → Phosphorylation of specific residues on
eNOS
39. 2. Natriuretic Peptide Receptors
3 small peptide ligands:
Atrial Natriuretic Peptide (ANP):
• Released from atrial storage granules
• ↑ Intravascular volume/ Stimulation with pressor hormones
Brain Natriuretic Peptide (BNP):
• Synthesized and released from ventricular tissue
• Volume overload
40. C-type Natriuretic Peptide (CNP):
• Synthesized in brain & endothelial cells
• Growth factors/ stress on vascular endothelial cells
Major physiological effects:
↓ BP (ANP/BNP)
↓ Cardiac hypertrophy & fibrosis (BNP)
41. Receptors with intrinsic enzymatic activity
3 types of receptors:
1) ANP Receptor (NPR-A)
Binds to ANP & BNP
Maintaining normal state of CVS
2) BNP Receptor (NPR-B)
Binds to BNP
Role in bone function
3) CNP Receptor (NPR-C)
No enzymatic activity
42. Ligand brings juxtamembrane regions together
Phosphorylation of serine residues→
Stimulation of guanyl cyclase
43. Guanylate Cyclase:
Membrane-bound (type 1) & soluble (type 2) forms
Membrane bound→ activated by ligands
Soluble→ activated by NO
Catalyzes reaction of
GTP to cGMP
44. Downstream reactions of cGMP:
Activation of Protein Kinase G
cGMP gated ion channels
cGMP-modulated Phosphodiesterase
45. cGMP-dependent protein kinase or Protein Kinase G
(PKG)
Serine/threonine kinases
PKG I → cytoplasm, PKG II → membrane associated
PKG I→ smooth muscles, platelets, brain
PKG II→ intestines, bones, kidney
Regulatory and catalytic domains contained on a single
polypeptide chain
Upon activation dimerizes to form PKG holoenzyme
46. Actions of PKG I:
Inhibits of Gq/G11→ Inhibition of Phospholipase C→ ↓ Ca2+
Inhibits G12/G13→ Inhibits Ca2+ sensitizing mechanisms
Phosphorylates and inhibits the Myosin light chain
kinase which normally phosphorylates the myosin light
chains
47. Effects:
Relaxes all smooth muscle types
Inhibits platelet aggregation & granule secretion
Functions of PKG II:
Stimulates in chloride & water secretion in small intestine
Normal endochondral bone development
Inhibits renin secretion
48. Therapeutic Applications
1. NO Donors
Organic nitrates
• Short acting: Nitroglycerin (NTG)
• Long acting: Isosorbide mononitrate, Isosorbide dinitrate,
Pentaerythritol tetranitrate
• Use: Treatment of Angina
• A/E: Tolerance (Nitrate free interval)
49. Sodium Nitroprusside
• Hypertensive emergencies
Nicorandil
• K+ channel opner and NO donor
• Antianginal
CCB’s: Nitrendipine, Nifendipine, Lacidipine
• Dihydropyridine
• Release NO
• Retard atherosclerosis
• Use : Hypertension, angina
51. BAY series of compounds
8-bromo-cGMP
8-bromoPET-cGMP
8-pCPT-cGMP
Specific activators & inhibitors of cGKI & cGKII
Improve the specificity & availability of treatment
Evaluated for:
• Asthma
• Graft survival after liver & lung transplantation
52. Phosphodiesterases (PDE)
PDE comprise family of enzymes expressed in almost all cells
of the body & of prime importance in cellular functioning
Hydrolysis of phosphodiester bond in the second messengers
c AMP & c GMP → inactive forms 5 AMP and 5 GMP
respectively
53. Reversal of activation of cellular protein kinases
Inactivation leads to termination of intracellular signals
Regulators of cyclic nucleotide signaling & responsible for
diverse physiological functions
PDEs comprise a super family composed of 25 genes
Categorized into 11 sub families i.e. PDE 1 – PDE 11
Substrate specificity:
c AMP
Specific
c GMP
Specific
cAMP & cGMP
Specific
• PDE 4
• PDE 7
• PDE 8
• PDE 5
• PDE 6
• PDE 9
• PDE 1
• PDE 2
• PDE 3
• PDE 10
• PDE 11
54. Act by modulating the levels of 2nd messengers
Therapeutic Applications:
Congestive heart failure:
PDE-3 Inhibitors→ Amrinone, Milrinone
↑ In force of contraction
Direct vasodilation of both the resistance & capacitance vessels
Inodilators
55. Erectile dysfunction:
PDE-5 Inhibitors→ Sildenafil, Tadalafil, Vardenafil
Never combined with nitrates:
• Nitrates produce vasodilatation by NO dependent elevation
of cGMP in vascular smooth muscle
• Thus PDE 5 inhibitor if given along with of a NO donors can
cause profound & extreme hypotension
• Pts should be asked for a history of nitrate consumption within
previous 24 hrs
60. Three Types of Inositol phospholipids:
PI, PI(4)P, PI(4,5)P2
61. Phospholipase C exists as 2 isoforms:
1. Phospholipase Cβ:
• Activated by GPCRs couple to Gi/Gq→ release GTP bound
α subunit & βƔ dimer→ both activate
2. Phospholipase CƔ:
• Activated by Receptor/Non Receptor Tyrosine Kinases
Cytosolic enzymes
Translocate to plasma membrane on receptor activation
Ligands:
AGT, GnRH, GHRH, Oxytocin, TRH
62. Phospholipase C forms Diacylglycerol & Inositol 1,3,5- triphosphate
from Phosphotidyl Inositol 4,5-bisphosphate
63. Protein kinase C:
Regulatory domain & catalytic
domain tethered together by a
hinge region
C1 domain, present in all of the
isoforms of PKC has a binding site
for DAG
C2 domain acts as a Ca2+ sensor
Catalytic Region brings about
phosphorylation Ser/Thr a.a. of
proteins
Upon activation, translocated to the
plasma membrane
66. IP3 Receptor
Ligand gated Ca2+ channel
High conc. in membrane of ER
Ligands which regulate:
1. PKA:
↑ Ca2+ release by phosphorylation
2. PKG:
• Inhibits Ca2+ release
3. IP3:
• ↑ Ca2+ release
4. Ca2+:
• Conc of 100-300nM→ ↑ Ca2+ release
• Conc of 1000nM→inhibits Ca2+ release
• Oscillatory pattern of Ca2+ release
67. Ryanodine receptor
Present in skeltetal & cardiac muscles
& neurons
Major cellular mediator of
calcium-induced calcium release
Ca2+ enters through L-type Ca Channels
Conformational change in RyR receptors
Release of Ca2+ from SR into cytosol
Agonist: Xanthines (Caffeine, Pentoxyfylline)
Antagonist: Dantrolene
68. Calcium Reuptake
Na+/Ca2+ exchanger on plasma membrane
Ca2+ pump on ER membrane
Ca2+ binding molecules
Ca2+ pump on Mitochondia
69. Cell Type Effect
Secretory Cells (mostly) ↑secretion (vesicle fusion)
Juxtaglomerular cells ↓secretion
Parathyroid chief cells ↓secretion
Neurons
transmission (vesicle
fusion)
T-cells
activation in response to
antigen presentation
Myocytes Contraction (TroponinC)
Effects of Ca2+ :
70. Calmodulin binds Ca2+ & activates 5 different
Calmodulin-dependent kinases
1. Myosin light-chain kinase→ Phosphorylates myosin→
Contraction in smooth muscle
2. CaMK I → synaptic function
3. CaMK II → neurotransmitter secretion, transcription factor
regulation & glycogen metabolism
4. CaMK III → protein synthesis
5. Calcineurin, a phosphatase that inactivates Ca2+ channels
by dephosphorylating prominent role in activating T cells →
inhibited by some immunosuppressants
71. Therapeutic Applications:
Drug Mechanism of
Action
IP3/DAG
Levels
Therapeutic
Application
Prazosin α1 blocker ↓ Hypertension/
Prostate
Hyperplasia
Chlorpheni-
ramine
H1 blocker ↓ Allergies/
Common cold
Ipratropium
bromide
M3 blocker ↓ Asthma/ COPD
Losartan AT1 Receptor
blocker
↓ Hypertension/
MI/ Diabetic
Nephropathy
Montelukast LT C4/D4 blocker ↓ Asthma
Oxytocin Direct action on
Gq
↑ Labour induction/
Uterine inertia
72. Cell surface receptors recruit activity of protein kinases in two general ways:
Receptor Tyrosine Kinases:
Possess an intrinsic tyrosine kinase activity that is part of the receptor protein
Examples include receptors for growth factors (PDGF, EGF, insulin, etc.)
Non-receptor tyrosine kinases:
Receptors lacking self-contained kinase function
recruit activities of intracellular protein kinases to the plasma membrane
73. Receptor Tyrosine Kinases
Implicated in diverse cellular responses:
Cell division, Differentiation & Motility
At least 50 RTKs identified:
Subdivided into 10 subclasses based on
differences within extracellular, ligand-binding domain of receptor
74. Structure:
Four common structural features shared
among RTKs
Extracellular ligand-binding domain
Single transmembrane domain
Cytoplasmic tyrosine kinase domain(s)
Regulatory domains
75. Receptor Dimerisation
Three ways in which signaling proteins can cross-link receptor
chains
1. Dimer ligand
2. Monomer but brought together by proteoglycan
3. Cluster on membrane
76. Receptor dimerization leads to activation of
catalytic domains causing
autotransphosphorylation
Receptor autotransphosphorylation:
• Further stimulates kinase activity
• Leads to phosphorylation of additional
proteins involved in receptor
signalling pathway
77. Provides “docking sites” for downstream
signalling proteins
(Grb2, PI3-kinase, phospholipase C , etc.)
Src homology (SH) 2 & SH3 domains:
SH2 domains: bind P-Tyr-containing sequences
SH3 domains: bind to pro-rich (PxxP) sequences
Activates Phospholipase CƔ
The binding of SH2-containing intracellular signaling
proteins to an activated PDGF receptor
80. Ras-Raf-MAP kinase pathway in Cancer
Ras gene mutation→
defective Ras protein
GAP binds to GTP bound Ras, but
not able to provide domain for GTPase
GTP is not lysed & the GTP bound
Ras remains continuously active
Thus permanently activated MAP kinase pathway
results in growth factors transcription causing continuous cell
proliferation
Development of Cancer
81. 2. PI3 Kinase Pathway
Activated PI3 docks at the
phosphorylated RTK
Brings about phosphorylation of
PIP2→PIP3
Downstream effects:
• Inhibits proapoptotic protein BAX
• Translation of tumour proteins by
activation of mTOR
• Phosphorylation of FOXFO, antitumour protein,
→ ubiquitinisation→ degradation
82. Therapeutic Applications
I. Receptor Tyrosine Kinase Inhibitors:
A. Epidermal Growth Factor Receptor Inhibitor/ HER 1 Inhibitor
Geftinib:
• Inhibits EGFR tyrosine kinase activity
• Blocks ATP binding site
• NSCLC pts. who have failed with std. chemotherapy
Erlotinib
• Similar mechanism of action
• Locally advanced or metastatic NSCL & Pancreatic Ca
83. Cetuximab:
• Monoclonal antibody to extracellular domain of EGFR
• Combined with Radiation for Locally advanced
Squamous Cell Ca of head & neck
• EGFR positive metastatic Colorectal Ca
Panitumumab:
• Recombinant fully humanized IgG to extracellular domain
of EGFR
• EGFR positive metastatic Colorectal Ca
84. B. HER2/neu Inhibitor
Lapatinib
• Inhibits EGFR & HER2/neu Kinase activity
• ATP binding pocket
• Approved for Trastuzumab Refractory breast Ca with
Capecitabine
Trastuzumab:
• Humanized monoclonal Antibody to external domain
of HER2/neu receptor
• Her2/neu overexpressing metastatic breast Ca
with Paclitaxel
85. II. mTOR inhibitors:
IL-2 stimulates immune system by activation of T Cells via
activation of mTOR
Sirolimus (Rapamycin)
Binds to mTOR & inhibits action of IL-2
Immunosuppressive agent in organ transplant & GVHD
Cardiac stents to ↓ chances of re-occlusion
A/E: thrombocytopenia, hyperlipidemia, HUS
Everolimus
Short t1/2
Cardiac transplants
86. JAK-STAT Receptor Pathway
Ligands: Interferon Ɣ, Growth hormone, Prolactin
Receptors have no intrinsic activity
Intracellular domain binds intracellular tyrosine kinase→
Janus Kinase (JAK)
Receptor mediated dimerization → phosphorylation of
Signal transducers & activators of transcription (STAT)
STATs translocate to nucleus & regulate transcription
4 JAKs & 6 STATs combine differently depending on
Cell type & signal
Eg: Prolactin→ JAK1, JAK2 & STAT5
88. Receptor Serine-Threonine Kinases:
Anologous to RTK except they have
Serine/Threonine kinase domain in cytoplasmic region
Ligand: TGFβ
Dimerizes in presence of ligand→
Phosphorylation of kinase domain→ activation
Phosphorylation of gene regulatory protein termed
Smad on serine residue
Dissociates from receptor→ associates with transcription factors
→ Morphogenesis & transformation
Inhibitory Smads: Smad6/7
89. Toll like Receptors
Signaling related to innate immunity
Family of 10 receptors
Structure:
• Single polypeptide chain
• Large extracellular ligand binding domain
• Short membrane spanning domain
• Cytoplasmic TIR domain
Ligands: Pathogens (lipids, peptidoglycans, lipopeptides,
viruses)
Inflammatory response to pathogen
90. Signaling:
Receptor induced dimerisation
Recruitment of Mal & MyD88 to TIR
Recruits Interleukin-associated kinases
(IRAKs)
Auotphosphorylates & complex with MyD88
Also recruits TRAF6
Interact with protein kinase TAK1 & Adaptor TAB1
Activates NF-КB
Trasncription of inflammatory genes
92. Has following effects:
Activation of NF-κB:
• Transcription of proteins involved in cell survival and
proliferation, inflammatory response & anti-apoptotic factors
Activation of the MAPK pathways:
• The JNK pathway is involved in cell differentiation,
proliferation & is pro-apoptotic
Induction of death signalling:
• Cell apoptosis
93.
94. Therapeutic Application
Promotes inflammatory response & associated with
autoimmune disorders:
(Rheumatoid arthritis, ankylosing spondylitis, inflammatory
bowel disease, psoriasis, hidradenitis suppurativa and
refractory asthma)
Treated by using a TNF inhibitor:
• Monoclonal antibodies such as
Infliximab, Adalimumab & certolizumab pegol
• Circulating receptor fusion protein such as etanercept
95. Pharmacodynamic Interactions in a Multicellular
Context
Consider the vascular wall of an arteriole
Several cells interact at this site:
Smooth muscle cells(SMC), endotheial cells, platelets & post-
ganglionic parasympathetic neurons
Effects produced
• SMC contraction→ Ang II, NE
• SMC relaxation→ NO, BNP, epinephrine
• Alter gene expression→ PDGF, Ang II, NE, Eicosanoids
96. Patient with hypertension
• ↑ levels of AngII
• ↑ activity of sympathetic nervous system
• ↓ NO production
Pharmacotherapy directed towards:
• ↓ BP
• Prevent long term changes in vessel wall
Drugs used to treat hypertension
• ↓ Ang II (Atenolol/Aliskiren/Enalapril/Losartan)
• α1 blockers→ ↓ NE binding on SMCs
• ↑ NO production (Na Nitroprusside)
97.
98. Conclusion:
Second messengers have shown to play physiological &
pathophysiological settings
Evolved as targets for drug develoment for numerous diseases
However, availability of compounds acting on specific targets is
the biggest challenge
Also is their difficult expression & purification
Such specific drugs are still in their early stages of development
„Today‟s drug targets, tomorrow‟s blockbusters‟
Editor's Notes
G0- ↓ ca entry into cells
Guanine exchange factors
To form heterotrimer
GEF- Guanine exchange factors
Conformational change
substrates
The protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca++-ATPase (SERCA) in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca++ pump leads to shorter intervals between contractions, thereby contributing to the inotropic response
stimulate lipase[
Brain-derived neurotrophic factorbinds to certain DNA sequences called cAMP response elements (CRE) thereby increasing or decreasing the transcription of the downstream genes
GEFs: proteins involved in the activation of small GTPases
More efficacious & mimic action of several neurotransmitters; in neurodegenrative disorders
desensitization
gram positive and negative bacteria,tumor cells and heterologous antigens; involved in transplantation
Inhibition of IP3 receptors by phosphorylation of IP3 receptor associated cGMPkinase substrate… Phosphorylation of phospholamban- stimulate SERCA (sarcoendoplasmic reticulum pump Ca ATPase
administered intravenously usually by bolus followed by IV infusion
which is caused by this 2nd messengers
Resistance-atrerioles, small arteries and capillaries; Capacitance- veins ie they hold blood
When activated hydrolyse minor membrane phospholipidPhosphotidyl-inositol 4,5 biphosphate to generate 2 intracellular signals: IP3( Inositoltriphosphate) & Diacylglycerol(DAG)
Gq
Protein kinase G (cGMP)
Increasein the sensitivity of RyRs to Ca2+
the gitsecretes digestive enzymes & gastric acid, the lungsecretes surfactants & sebaceous glands secrete sebum
Via activation of kinases mek1/2 & erk1/2; activation of trascription factors of AP1(activator protein) family if fos/jun- growth factors
OncogenicRas
Viz present in the plasma membrane; which causes apoptosis by forming holes in mitochondria,
Mammilian target of rapamycin
mechanisms that defend the host from infection by other organisms in a non-specific manner.does not confer long-lasting or protective immunity to the host; TIR no enzymatic activity
Myeloid differention protein 88
TRADD recruits TRAF2 and RIP. TRAF2in turn recruits the multicomponent protein kinase IKK, enabling the serine-threoninekinase RIP to activate it.TRADD binds FADD, which then recruits the cysteine protease caspase-8