Metabotropic receptors (DONE)

Question 1

What are metabotropic receptors?

Answer 1

G-protein coupled receptors
Mediate cellular response to neurotransmitters and hormones
Directly responsible for senses of sight, smell and taste
~1% human genome comprises DNA encoding GPCRs
40-50% of all currently marketed drugs activate the GPCR

Question 2

Classes of metabotropic receptors

Answer 2

Rhodopsin-like 7 transmenebrane segment (>300)
Secretin receptors (approx. 34)
Metabotropic receptors (22)

Question 3

Secretin family

Answer 3

Calcitonin receptor family, glucagon receptor family, corticotrophin release hormone receptors, parathyroid hormone receptors, vasoactive intestinal peptide receptors
Over 20 members
Area of most diversity in family
All receptors stimulate AC and couple to G proteins

Question 4

Secretin receptors

Answer 4

All have a hormone binding domain and bind peptide hormones
Four targets are used clinically:
Calcitonin to treat hypercalcaemia
Glucagon to treat hypoglycaemia
GLP-1a agonists for glucose regulation
Parathyroid hormone to treat osteoporosis
Central homeostatic function- good target for other future drugs

Question 5

Rhodopsin

Answer 5

Abundant in retina
Easier to study than receptor proteins
Activated by proteins
Photon produces response rather than agonist

Question 6

Metabotropic Glu receptors e.g. GABA-B

Answer 6

Contains receptors for:
8 metabotropic glutamate receptors
Ca sensing receptor
2 GABA-B receptors
Taste receptors
7 orphan receptors

Question 7

Functions of metabotropic glu receptors

Answer 7

Group 1 are mostly post-synaptic, groups 2 and 3 are mostly presynaptic autoreceptors
Modulate other receptors
Modify excitotoxic activity (NMDA receptors)
Involved in synaptic plasticity
Differential distribution in the brain

Question 8

What does the heterotrimeric G-protein do?

Answer 8

Recognises the active receptor and reacts with the effector
Family of membrane resident heterotrimeric G proteins consisting of A and BG subunits
Bind GTP and GDP

Question 9

How does an activated G-protein coupled receptor influence cell function?

Answer 9

Agonist binds to receptor
G-protein interacts with activated receptor and GDP exchanged for GTP, subunits dissociate
Activated A subunit interacts with other signalling molecules
RGS proteins enhance hydrolysis of GTP to GDP
A subunit inactivated and recycled

Question 10

How do agonists and antagonists stabilize receptor conformations?

Answer 10

7TM receptors- have some activity without ligand, increased with ligand, allosteric modulation
Agonists- stimulate the receptor by stabilizing an active conformation
Antagonists- stabilize one or more of the many different inactive conformations

Question 11

Complexities of G-protein signalling

Answer 11

Some GPCRs are constitutively active e.g. adrenoceptors
Inverse agonists- decrease binding and reduce basal activity and binding affinity
Allosteric modulators

Question 12

Homodimerisation

Answer 12

Many GPCRs form dimer to express function
May be via covalent or non-covalent interactions and may involve extracellular domains and or C terminal tails
Complex interactions with multiple G-proteins

Question 13

Heteromeric dimerisation

Answer 13

Independently cloned, recombinant monomers/ homomers not functional, function requires heteromeric expression
Increases functional diversity economically

Question 14

Heterotrimeric G Protein Diversity

Answer 14

G proteins derived from large gene family
A given subtype may have more than one isotype
In mammals there are 5 distinct B-subunits and several different G subunits

Question 15

How to terminate signalling events

Answer 15

Stop production of ligand
Modify receptor to prevent further ligand binding
Remove receptor and ligand by receptor mediated endocytosis
Remove second messenger
Remove phosphate groups from target proteins

Question 16

Desensitisation

Answer 16

Homologous desensitisation is specific- only the active receptor is phosphorylated by GRKs
Promotes binding of the arrestin which sterically inhibits the interactions between the receptor and g-protein
Heterologous desensitisation- kinases activated phosphorylate other receptors in the same membrane

Question 17

Long term desensitisation

Answer 17

After repeated or prolonged downregulation, delivered to lysosomes and degraded after internalisation
Gene transcription may be down regulated to stop production of new receptors
Results in a decreased response over hours
RGS proteins may be changed- GTPase activating proteins accelerate the rate of GTO hydrolysis- speeds up receptor deactivation

Question 18

Consequences of receptor desensitisation

Answer 18

Desirable and undesirable
Changing the magnitude of the response
Increasing medications
Tolerance to the drug
Dependence

Question 19

Similarities of metabotropic and ionotropic receptors

Answer 19

Some transmitters have both receptor subtypes
Cause a physiological effect
Agonists and antagonists
Modulation

Question 20

Differences between metabotropic and ionotropic receptors

Answer 20

Structure
Function/ action
Speed of activation/ desensitisation
Potential for signal amplification