Catalytic receptors Flashcards
give examples of the major catalytic receptor families
Receptor tyrosine kinase (RTK)
Receptor guanylyl cyclase (RGC)
Receptor serine-threonine kinase (RTSK)
Receptor tyrosine phosphatase (RTP)
Receptor guanylyl cyclase structure
EC peptide binding domain, intracellular guanylyl cyclase enzymatic domain. 1 TM region. forms homodimer.
what is RGC’s function
Catalyses conversion of GTP to cGMP, which activates PKG to phosphorylate proteins, causing cellular responses.
what are the endogenous agonists of RGC and what do they modulate
ANP
BNP
CNP
uroguanylin
guanylin
e. coli sta1
Uroguanylin and guanylin found in GIT, and bind to RGC-C to elevate cGMP, phosphorylating apical Cl- channels causing influx of cl- into GIT. Water follows the ions - fluid secretion into GIT.
E.coli Sta1 is a potent agonist in the GIT, the water secretion that follows causes diarrhoea. (rgc-c receptors)
Uroguanylin also secreted following large salt intake, to activate the renal RGCs leading to increased Na+/K+ channel function (sodium into tract potassium out into blood) aiding in diuresis. electrolyte homeostasis.
ANP is secreted in vasculature following atrial wall stretch. causes vasodilatation, increases urinary Na+/K+ excretion/diuresis, and a reduction in blood pressure.
Soluble guanylyl cyclase structure
A member of the RGC family. Formed by heterodimer of alpha1beta1 and alpha2beta1. Contains haem. NO activates it.
RGC exploitation
Nesiritide is a RGC-A agonist (recombinant) for decompensated congestive heart failure. increases BV diameter and water loss by kidneys.
Linacotide is a RGC-C agonist (analogue of E.coli Sta1) for chronic constipation in IBS
Plecanatide. is a RGC-C agonist (uroguanylin analogue) for chronic idiopathic constipation.
Organic nitric oxide donors (E.g., GTN: glycreyl trinitrate) for soluble guanylyl cyclase for angina
riociguat is a soluble guanylyl cyclase activator for pulmonary artery hypertension.
describe RTK family structure and what happens upon ligand binding
include EGF-R, Ins-R, PDGF-R, and FGF-R. total of 58 RTKs.
Contain EC protein binding domain, IC PTK catalytic activity. Mostly form homodimers. has 1 TM region.
Upon ligand binding, the receptor autophosphorylates, and interacts with intracellular accessory proteins to activate MAP kinase, PLC-gamma, and PI 3-kinase. All 3 pathways associated with cell growth/proliferation.
MAP kinase cascade (RTK)
Initiated by conversion of GDP to GTP, which activates raf, consequently activating MEK then MAP kinase. This leads to gene transcription and protein phosphorylation events.
Turned off by MAP kinase phosphatase.
PLC-gamma signalling (RTK)
Activation of PLC-gamma cleaves PIP2 into DAG and IP3. This increases IC [Ca] (by mobilizing intracellular calcium stores) and causes protein phosphorylation.
Turned of by IMPase.
PI 3-kinase (RTK)
PI 3-kinase converts PIP2 to PIP3, which in turn activates PKC-Z and PDK1. PDK1 activates PKB. This cascade leads to protein phosphorylation. PDK1 increases glucose uptake (GLUT4-mediated), increases glycogen synthase kinase which converts glucose to glycogen and increases glycolysis via increasing phosphofructokinase generating ATP.
Turned of by PTEN, which converts PIP3 back to PIP2.
give examples for RTK exploitation
Larotrectinib is a NRTK1 inhibitor to treat NRTK-mediated advanced solid tumours.
Imatinib is an inhibitor of several RTKs, used to treat cancers
RTP structure and function
12 in humans. Have EC binding domain, and IC RTP catalytic domain. 1 TM region.
Upon binding, IC accessory proteins are dephosphorylated, and they then regulate phosphorylation cascades, potentially to oppose RTK function.
RSTK structure and function
17 in humans. Heterodimers. 1TM domain, EC receptor domain, IC serine/threonine catalytic domain. Phosphorylates the IC protein Smad, which heterodimerises and regulates gene transcription by binding to mRNA.
