WHAT A LADD Flashcards
(1) Structure of GPCRs
- 7 transmembrane domains
- Exoplasmic N-terminal binds ligand
- Cytoplasmic loop 3 interacts with G protein
- Cytoplasmic C-terminal tail involved in regulating GPCR
(1) 3 main mammalian GPCR subfamilies
A: Rhodopsin-like group (most of GPCRs)
B: Secretin receptor family
C: Venus fly trap: Metabotropic gluatmate and GABAa receptor family
(1) VAS IS DAS Orphan receptors
GPCRs that are identified which family they are in by homology cloning but unknown activating ligand
(1) What are RGS
Regulators of G protein signalling
(1) G proteins and 2nd messenger
Gs = mediated by alpha (adenylyl cyclase + Ca2+ channels) Gi = alpha = inhibits adenylyl cyclase Gq = alpha = activates phospholipase C-B
(1) G-protein cycle thingy
1) Resting (GDP-bound) state
2) Ligand binding and nucleotide exchange in Ga (GDP to GTP)
3) Active (GTP-bound state)
Ga dissociates and binds effector
GB and Gy bind other effector (Internal signalling occurs
4) GTPase activates
RGS binds Ga (GTP to GDP)
5) Ligand dissocaition, G-protein timer formation
(1) Common experimental tools used to study GPCRs
1) Cholera toxin
-Causes ADP ribsoylation of Gas
-Prevents GTP hydrolysis
-ALWAYS activating adenylate cyclase
-Lots of cAMP
DEATH
2) Pertussis Toxin (PTX)
- Causes ADP ribosylation of Gai
- Prevents release of GDP. INACTIVE
- Prevents inhibition of adenylate cyclase
- Same as cholera
(1) RGS proteins function
Negative regulators of G protein signalling
-Enhance Ga proteins intrinsic GTPase activity
(1) Regulation of GPCR function
1) De/resensitisation: Decrease in responsivness during continous drug application (right-shift in drug dose response curve)
- Long term desense: Changes in G protein levels, mRNA expression
- Rapid desense: Receptor phos, arrestin binding, receptor internalisation
(1) 2 types of densensitisation
Heterologous desense: 2nd messneger kinase (PKA/PKC) = Then arrestin bindig
Homologous desense: G-protein coupled receptor kinase (GRK)
B-arresting binding to phos GPCR is required to decrease GTPase activity prior to densense
(1) Arrestin mechanisms
- Promotes uncoupling of G protein
- Desense by binding to clathrin and calthrin adaptor protein AP2
- Promotes G-protein independent signalling
(1) GPCR heterodimers
Family C GPCRs
ALSO Rhodopsin homodimers
(e.g. Vasopressin and OT Rs)
(1) VAS IS DAS Orthosteric site
The site where agonists and antagonists bind to on a GPCRs
PAM: Positive allosteric modulator
NAM: Negative allosteric modulator
(1) VAS IS DAS Signal bias
GPCRs have a preference and higher affinity for certain ligands over other and produce a greater response to them.
(2) Diabetes
A metabolic disorder of multiple aetiology characterised by chronic hyperglyceamia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion or action or both.
(2) Type 1 diabetes treatments
1) Islet transplantation
2) Insulin
3) Diet, exercise
4) Lifestyle
(2) Type 2 diabetes treatments
1) Lifestyle
2) Diet, exercise (decrease fat content as its assocaited with increased insulin sensitivity)
3) Oral monotherapy
4) Oral combination therapy
5) Insulin (with or without oral agent)
(2) Supplemtments in type 2 diabetes
1) statins: Stop liver cholesterol
2) Fibrates: Less effective lowering LDL, improve HDL and triglyceride levels). Improve insulin resistance
3) Resins: Bind cholesterol
4) Orlistat: Inhibits pancreatic lipase, prevent triglyceride digestion from gut. Decreases fat absorption
(3) GLP-1 effects in humans
1) B cell: Enhances glucose-dependent insulin secretion
2) A cell: Suppresses postprandial glucagon secretion
3) Liver: Reduces hepatic glucose output
4) Stomach: Slows rate of gastric emptying
5) Brain: Promotes satiety and reduces appetite
(3) Treatments of Hyperglycaemia
1) Increased carbohydrate intake: Alpha glucosidase inhibitors
2) Decreased Insulin secretion: Sulphonylureas
3) Decreased pheripheral glucose uptake (insulin resistance): Metformin / Thiazolidinediones
4) Increased hepatic glucose output: Metformin (Glucophage)
(3) How Thiazolidinediones work
1) Bind PPARy nuclear receptor
2) PPARy complexes with Retinoid X receptor (RXR)
3) Enhances insulin selective genes (e.g. GLUT-4 and Lipoprotein lipase)
RESULT: Increased glucose uptake and lipogenesis and decreased circulating fatty acids
(3) How metformin works
-Its a biguanide
-Unchanged by kidneys
ACTION
1) Reduces hepatic gluconeogenesis
2) Decreased absorption of glucose from GI tract
3) Increased insulin sensitvity by increasing peripheral glucose uptake and utilisation
(3) How Alpha-glucosidase inhibitors work
Act as competitive inhibtors of enzymes required to digest carbohydrates.
- Used to decrease current blood glucose levels
(e. g. Acarbose)
