WHAT A LADD Flashcards

1
Q

(1) Structure of GPCRs

A
  • 7 transmembrane domains
  • Exoplasmic N-terminal binds ligand
  • Cytoplasmic loop 3 interacts with G protein
  • Cytoplasmic C-terminal tail involved in regulating GPCR
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2
Q

(1) 3 main mammalian GPCR subfamilies

A

A: Rhodopsin-like group (most of GPCRs)
B: Secretin receptor family
C: Venus fly trap: Metabotropic gluatmate and GABAa receptor family

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3
Q

(1) VAS IS DAS Orphan receptors

A

GPCRs that are identified which family they are in by homology cloning but unknown activating ligand

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4
Q

(1) What are RGS

A

Regulators of G protein signalling

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5
Q

(1) G proteins and 2nd messenger

A
Gs = mediated by alpha (adenylyl cyclase + Ca2+ channels)
Gi = alpha = inhibits adenylyl cyclase
Gq = alpha = activates phospholipase C-B
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6
Q

(1) G-protein cycle thingy

A

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

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7
Q

(1) Common experimental tools used to study GPCRs

A

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

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8
Q

(1) RGS proteins function

A

Negative regulators of G protein signalling

-Enhance Ga proteins intrinsic GTPase activity

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9
Q

(1) Regulation of GPCR function

A

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

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10
Q

(1) 2 types of densensitisation

A

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

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11
Q

(1) Arrestin mechanisms

A
  • Promotes uncoupling of G protein
  • Desense by binding to clathrin and calthrin adaptor protein AP2
  • Promotes G-protein independent signalling
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12
Q

(1) GPCR heterodimers

A

Family C GPCRs
ALSO Rhodopsin homodimers
(e.g. Vasopressin and OT Rs)

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13
Q

(1) VAS IS DAS Orthosteric site

A

The site where agonists and antagonists bind to on a GPCRs
PAM: Positive allosteric modulator
NAM: Negative allosteric modulator

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14
Q

(1) VAS IS DAS Signal bias

A

GPCRs have a preference and higher affinity for certain ligands over other and produce a greater response to them.

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15
Q

(2) Diabetes

A

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.

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16
Q

(2) Type 1 diabetes treatments

A

1) Islet transplantation
2) Insulin
3) Diet, exercise
4) Lifestyle

17
Q

(2) Type 2 diabetes treatments

A

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)

18
Q

(2) Supplemtments in type 2 diabetes

A

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

19
Q

(3) GLP-1 effects in humans

A

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

20
Q

(3) Treatments of Hyperglycaemia

A

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)

21
Q

(3) How Thiazolidinediones work

A

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

22
Q

(3) How metformin works

A

-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

23
Q

(3) How Alpha-glucosidase inhibitors work

A

Act as competitive inhibtors of enzymes required to digest carbohydrates.

  • Used to decrease current blood glucose levels
    (e. g. Acarbose)