- cross PM only once via alpha helix - monomers or dimers (tyrosine kinase) - no direct G proteins/not serpentine!
Enzyme-linked (or catalytic) Receptors
(1) receptor itself has a latent enzyme activity that is activated when the receptor’s specific agonist binds, or (2) it activates other intracellular proteins that are latent enzymes
Types of Catalytic Receptors:
•Receptor guanylylcyclases (-->cGMP)
•Receptor tyrosine kinases (RTK)
–Growth,proliferation, differentiation, survival, and cell motility factors
••Receptor tyrosine phosphatases
– Membrane-bound guanylylcyclases (GC);
– The more common form of receptor GC is a soluble (cytoplasmic) protein that is the target, throughout the body, for the messenger nitric oxide.
Membrane bound GC examples
- DA of midbrain; ADHD - ANP
Soluble GC: Nitric oxide
- regulation of blood flow and blood pressure - NO is membrane soluble but unstable - works thru activation of soluble GC so the cyclase is the receptor
Nitric oxide synthase
•NO is synthesized by the enzyme nitricoxide synthase (NOS), which splits arginine into NO and citrulline.
•One isoform of NOS is constitutively active.A second is inducible and can be modulated.This inducible NO synthase, NOSi,is activated by high intracellular calcium.
Acts in cell it was made in or diffuses to nearby cells
extracellular (paracrine) first messenger OR
intraceullar second messenger
Stimulates GC -->inc cGMP levels
NO in vascular endothelial cells
• produced in vascular endothelial cells and diffuses to nearby smooth muscle cells, where it elevates cGMP, which causesvascular relaxation and vasodilation.
• Originally known as EDRF, endothelium-derived relaxation factor.
•Breaks down spontaneously to release NO. This causes (1) relaxation of arteriolar smooth musclein cardiac muscle,dilating the arterioles and increasingblood flow and oxygenation in the heart, and (2) relaxation of peripheral arterioles, which reduces peripheral resistance and so the work of the heart, both actions of which relieve the pain of angina pectoris.
- catalyzes transfer of a phosphate group (PO4) - either work solely with tyrosine residues or serines/threonines
- growth and differentiation - superfamily: inhibins, activins, bone morphogenic proteins, antimüllerian hormone - agonist binds to one of the two components of the enzyme - serine/threoninekinase - directly phosphorylate and activate cytoplasmic gene regulatoryprotein “SMADs”
TGF beta MOA
SMAD binds, gets P, binds second SMAD, translate to nucleus --> gene modulation
Receptor Tyrosine kinases
- two identical components of dimer
- Tyrosine kinase receptors have proven to be the receptors through which many growth factors, proliferation factors, differentiation factors, and survival factors work. - important in cancers
- two identical components of dimer - ligand binds, come together --> dimer - tyrosine its autophosphorylated at Y sites --> pY - intracell signalling proteins bind to pY - SH2,3 proteins are the first to bind - tyrosines bind to the complex and function as tyrosine kinases
- insulin - ILGF-1 - EGF - PDGF - NGF - FGF
RTK Activation Complexes
• Relay the “message” into the cell interior;
• The multiple proteins of an activation complex have multiple binding sites and can thereby bind to and sense inputs by a variety of intracellular components, including components of other transduction pathways.
RTK Activation Complexes cont
• In this way they function to integrate multiple and complex cell functions.
• Receptors that work in this way are important in coordinatingand regulating complex cell activities such as survival, growth, differentiation, proliferation, and motility.
Recognition of pY motifs by SH2 and SH3 domains
• The pY domains create high-affinity binding sites for intracellular proteins that contain “Src homology 2” (SH2) (“Src” is pronounced “sark”) or “Src homology 3” (SH3) domains. - SH2and SH3 differ in size and specificity from each other.Each in fact constitutes a family structurally related members.
RTK: intracellular signal recruitment
- different RTKs recruit different collections of intracell signaling proteins - some have SH2,3 domains - others may have PLC --> IP3 - some can activate PI3-kinase - MAPK (small G-proteins)
phosphatidyl-inositol 3-kinase (PI 3-kinase)
- phosphorylatesinositol phospholipids in PM
• IPs then become docking sites for other intracellular signaling proteins.
One of these is PK-B wh/ phosphorylatesserines and threonines on target proteins. - Important in signaling cells to survive and grow
Akt = PKB PKB helps in cell survival - GOOD
One action isto inhibit apoptosis - inactivates the "Bad" protein - Bad protein normally activates Bcl2 --> cell death
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