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Receptors
| Term | Definition |
|---|---|
| Glucocorticoid receptor characteristics | Cortisol (endogenous ligand), prednisolone, mifepristone -> stress hormone -> increase BGC, suppress immune system, aid fat/protein/CHO metabolism |
| Steroid ligand characteristics | Lipid soluble -> readily cross PM -> derived from cholesterol (mostly hydrophobic molecules apart from OH allowing PM entry), effects appear after lag phase and persist for hours/days |
| Steroid receptor characteristics | A/B - N-terminal regulatory domain, C - DNA binding domain, D - hinge region, E - ligand binding domain, F - C-terminal domain |
| Glucocorticoid receptor characteristics | Steroid receptor for cortisol, agonised by prednisolone, antagonised by mifepristone -> stress hormone -> increase BGC, suppress immune system, aid fat/protein/CHO metabolism |
| Mineralocorticoid receptor characteristics | Steroid receptor for aldosterone, agonised by fludrocortisone, antagonised by spironolactone -> homeostatic blood Pa regulation -> Na+ retained in kidney, salivary glands, colon, regulate kidney plasma K+ levels |
| Estrogen receptor characteristics | Steroid receptor for estradiol, agonised by ethinylestradiol, antagonised by tamoxifen -> sex hormone -> female reproductive system/2ndary sexual characteristic development/regulation, stimulate endometrial growth |
| Progestagen receptor characteristics | Steroid receptor for protesterone, agonised by norethisterone, antagonised by danazol -> sex hormone -> maintains endometrium, metabolic IM for production of other endogenous steroids, reduce aldosterone natriuretic effect |
| Thyroxine characteristics | Nucleic thyroid hormone receptor ligand, also known as tetraiodothyronine, small lipophilic molecule produced in thyroid gland by thyroglobulin proteolysis -> broad effects on cellular gene expression |
| Retinoic acid characteristics | Nucleic receptor ligand, small lipophilic molecule found in diet -> controls embryonic limb bud development/adult mammal skin regeneration |
| Transcription factor receptor characteristics | Nuclear receptor held inactive by chaperone proteins (hsp) -> receptor/steroid complex dissociates from hsp form obligate dimers -> phosphorylation -> binds to DNA-associated receptor -> activates/block transcription |
| Raloxifene | SERMS -> selective oestrogen receptor modulators -> nuclear steroid receptor inhibitors |
| Clompihene | Anti-oestrogens -> inhibit oestrogen binding in ant pituitary -> stops -ve feedback -> increase GnRH release -> nuclear steroid receptor inhibitors |
| nAChR characteristics | Pentamer of 2alpha, beta, gamma, delta subunits, both alpha subunits must be occupied by ACh, each subunit has 4 hydrophobic stretches (M1-4), M2 forms alpha helix, 5 M2 regions line pore of channel |
| Membrane guanylyl cyclase receptor characteristics | Dimer, ANP binds to extracellular face -> activates intracellular guanylyl cyclase domain to regulate blood Pa |
| RSK characteristics | Transmembrane proteins -> extracellular ligand-binding domains/cytoplasmic kinase domains -> signalling receptors for TGF-beta (transforming growth factor) superfamily of secreted polypeptides -> early embryogenesis, tissue homeostasis |
| RSK activation | Agonist binding to RSK II-> heteromeric type I/II complex -> II phosphorylates/activates I -> recruit/phosphorylate Smad2/3 -> dissociates/oligomerises w/ Smad 4 -> translocate complex to nucleus -> cell proliferation gene expression |
| RTK characteristics | Intracellular catalytic domain/extracellular regulatory domain -> receptor for insulin/EGF/PDGF -> all at some point activate small monomeric G protein Ras |
| EGF receptor structure/activation | RTK -> single polypeptide chain, agonist binding -> dimerisation -> autophosphorylation, v-erb B encodes truncated constitutively active EGF R |
| Insulin receptor | RTK -> beta, alpha, alpha, beta dimer |
| RTK activation | Agonist binding -> conformational change in extracellular domain -> intracellular autophosphorylation -> activate intrinsic Tyr K -> phosphorylate cascade of target enzymes |
| PDGF receptor characteristics | Split intracellular kinase domain, v-sis encodes PDGF chain -> increase growth factor signalling |
| Soluble kinase receptor characteristics | Agonist binding -> dimerisation -> JAK-STAT pathways, kinase domain encoded on separate gene from receptor but they associate together -> EPO receptor |
| GPCR characteristics | Single subunit receptors w/ 7 TMD alpha helices (ligand binding site w/in TM helices), extracellular N/intracellular C terminus, interact w/ G proteins via 3rd intracellular loop/C-terminal tail |
| Cholera toxin mechanism | ADP ribosylation of alpha-Gs -> inhibit GTPase activity -> sustained AC activation -> increases cAMP -> increaes PKA activation -> phosphorylate CFTR Cl- channel -> ATP mediated Cl- efflux -> H2O follows into intestinal lumen -> diarrhoea |
| Pertussis toxin mechanism | ADP ribosylation of alpha-Gi -> prevents Gi activation when GPCR stimulated -> interferes intracellular signalling -> AC uninhibited -> increase cAMP -> increase insulin secretion -> hypoglycaemia |
| Lithium | Noncompetitively inhibits IP1 phosphatase -> blocks inositol recycling/synthesis -> bipolar disorder treatment as brain depends on IP1 passage across BBB before recycling into inositol |
| GPCR desensitisation process | Uncoupling -> receptor phosphorylation uncouples G protein from receptor, sequestration -> receptores endocytosed from PM (returned/destroyed in lysosmes), down-regulation -> reduce # receptors for shuttling |
| Homologous desensitisation | Agonist binding to GPCR -> C-terminal domain end Ser/Thr phosphorylated by cytoplasmic GRK2/3 (beta-ARK1/2) -> increases affinity for beta-arrestin -> binds/uncouples receptor from alpha-Gs -> enables interaction w/ AP2/clathrin for GPCR internalisation |
| Why is it called homologous desensitisation? | GRKs can only act on agonist-occupied receptors -> desensitisation doesn't affect other present receptors |
| Heterologous desensitisation | Disproportionate GPCR stimulation -> AC -> cAMP -> high PKA -> phosphorylate 3rd cytoplasmic loop/1st part of C-terminal domain -> uncouples GPCR from alpha-Gs (prevent further stimulation) |
| Why is it called heterologous desensitisation? | PKA can phosphorylate receptors w/ similar aa to that of agonist-bound receptor -> desensitise other present receptors even if not ligand-bound |
| What is GPCR agonist bias? | The degree to which an agonist activates different pathways -> beta arrestin blocks beta2-AR G protein interaction but act as scaffolds for ERK1/2 activation |
| Oliceridine | mu-opioid receptor based agonist -> reduce beta-arrestin 2 recruitment/GPCR internalisation -> reduced adverse effects compared w/ morphine for pain relief |
| Why is agonist bias clinically important? | Drug may stop main signalling pathway from occuring but cause unwanted side effects if other pathways are activated by the drug-receptor bias |
| Special nAChR | CNS 5 alpha7 channel highly Ca2+ permeable -> most isoforms permeable to Na+/K+ |
| Muscle nAChR characteristics | 2 alpha1, beta2, delta, epsilon -> adult NMJ Fetal NMJ replaces epsilon w/ gamma subunit |
| Neuronal nAChR characteristics/locations | 2 alpha3, 3 beta2 -> autonomic ganglia 2 alpha4, 3 beta2 and 5 alpha7 -> CNS |
| mAChR characteristics | GPCRs mediating post-ganglionic PNS transmission |
| M1 location/function | mAChR -> slow EPSP at postganglionic ganglion, gastric acid secretion, ENS stimulation, CNS, vagal bronchoconstriction |
| M1 pathway | mAChR -> Gq/11 -> PLC -> PIP2 converted to IP3 and DAG -> ER Ca2+ influx/PKC activation -> CaM DAG can be activated by DAG lipase to produce AA -> precursor of PG/leukotrienes |
| Autonomic ganglion slow EPSP | Late depolarisation as postsynaptic M1 receptors inhibit K+ channel (depletion of PIP2/CaM and PKC activation) -> late depolarisation seconds after initial fast EPSP |
| M2 location/function | mAChR -> vagal heart stimulation, reduce atrial contractility, reduce AV node conduction velocity |
| M2 pathway | mAChR -> Gi-alpha -> decrease cAMP, Gi-beta/gamma -> open GIRK -> K+ efflux -> hyperpolarise membrane -> slow HR Atrial myocytes -> trigger IK-ACh -> K+ efflux -> hyperpolarisation -> reduce contractility |
| M3 location/function | mAChR -> bronchoconstriction, vascular dilation, pancreatic insulin secretion, salivary gland excretion, detrusor muscle relaxation |
| M3 pathway | mAChR -> Gq/11 -> PLC -> PIP2 converted to IP3 and DAG -> ER Ca2+ influx/PKC activation -> CaM -> MLCK Vascular endothelium -> CaM -> endothelial NO synthase -> smooth muscle soluble guanylyl cyclase -> cGMP -> hyperpolarise |
| M4 location/function/pathway | mAChR -> Gi/o -> inhibit ACh release in striatum -> extrapyramidal motor control (alter M4 may contribute to Parkinson's) |
| M5 location/function/pathway | mAChR -> Gq -> PLC -> PIP2 converted to IP3 and DAG -> ER Ca2+ influx/PKC activation -> dopamine inputs in substantia nigra/ventral tegmental area |
| alpha1 AR characteristics | Gq -> vasoconstriction, pupillary dilator muscle contraction, intestinal/bladder sphincter muscle contraction |
| alpha2 AR characteristics | Gi -> decrease sympathetic outflow, decrease pancreatic insulin release, decrease lipolysis, decrease aqueous humour production, increase platelet aggregation |
| beta1 AR characteristics | Gs -> +ve chrono/ionotropy, increase renin release, increase lipolysis |
| beta2 AR characteristics | Gs -> skeletal/coronary vasodilation, bronchodilation, increase lipolysis, increase insulin release, increase glycogenolysis, decrease uterine tone increase acqueous humour production, increase cellular K+ uptake, |
| beta3 AR characteristics | Gs -> increase lipolysis, increase skeletal thermogenesis, increase bladder relaxation |
| Receptors for insulin release | Increase insulin release -> beta2, M3 Decrease insulin release -> alpha2 |
| Receptors for vascular muscle tone | Vasoconstriction -> alpha1 Vasodilation -> beta2 - skeletal/coronary |
| Receptors for bronchial smooth muscle tone | Bronchodilation -> beta2 Bronchodilation -> M3 |
| Receptors for bladder muscle tone | Detrusor muscle contraction -> M2 Detrusor muscle relaxation -> beta3 Bladder sphincter contraction -> alpha1 |
| Receptors for pupil size | Dilation (mydriasis) -> alpha1 Constriction (miosis) -> M2 |
| Receptor for accommodation | M3 -> ciliary muscle contraction -> suspensory ligaments relaxed -> lens thick -> high refracting power -> short focal length (near objects) |
| Receptors for aqueous humour production | Increase production -> beta2 Decrease production -> alpha2 |
| Receptors for heart rate | Increase HR -> beta2 Decrease HR -> M2 -> also decreases atrial contractility |
| Gi receptors | M2, alpha2 |
| Gq receptors | alpha1, M1/3/5 |
| Gs receptors | beta1/2/3 |
| ATP receptors | A1, A2A/B, A3 -> metabotropic P2X 1-7 -> ionotropic P2Y 1, 2, 4, 5, 11-14 -> metabotropic |
| ATP A receptor isoform/function | Gs -> A2A/B -> relaxation of vascular smooth muscle Gi -> A1 (-ve chronotropic/ionotropic, presynaptic autoreceptors), A3 |
| P2X function | Mediate peripheral NANC transmission -> non-selective cation channels -> Na+/K+/Ca2+ permeable -> bind extracellular ATP |
| P2X isoform location | Neurons -> P2X 2/4/6 Smooth muscle -> P2X 1 |
| NO synthase isoforms | Neuronal (NOS I) -> expressed in CNS/NANC nerves, inducible (NOS II) -> expression induced by bacterial LPS/IFN-gamma (macrophages, fibroblasts, vascular smooth muscle cells), endothelial (NOS III) -> platelets/endothelial cells |
Created by:
vykleung
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