G-Protein Coupled Receptors

What is the largest family of cell-surface receptors that our sense of smell and taste depend on?

G-Protein Coupled Receptors (GPCRs)

How many GPCRs are present in the human genome?

More than 800 GPCRs.

What are GPCRs characterised by?

Seven membrane-spanning α-helical segments.

What do GPCRs use to relay signals into the cell?

They utilise G-proteins as molecular switches that activate various intracellular signalling pathways.

In the inactive state, what is α bound to?

GDP

What forms a stable trimer with α in the inactive state of GPCRs?

β and γ subunits.

What prevents α from interacting with effectors until activated?

The βγ dimer.

What occurs during GPCR activation?

Exchange of GDP for GTP on α.

What does the GPCR act as during activation?

A guanine nucleotide exchange factor (GEF).

What happens to α when it is activated?

It dissociates from βγ.

What type of proteins have covalently attached lipid tails to anchor them into the plasma membrane?

G-proteins.

What do RGS proteins bind to?

The active α–GTP subunit.

What do RGS proteins increase in GPCR signaling?

Intrinsic GTPase activity of α.

What is the effect of increased GTPase activity of α?

It converts GTP back to GDP faster.

What do GAPs do to GTP-binding proteins?

Inactivate them by stimulating hydrolysis of GTP to GDP.

What do GEFs do in relation to GTP-binding proteins?

Activate them by stimulating the release of GDP.

What are the two types of GTP-binding proteins?

Small monomeric GTP-binding proteins and trimeric GTP-binding proteins.

What are cyclic nucleotides examples of?

Secondary messengers.

What happens to cells when they are exposed to high concentrations of stimulating ligands?

They become desensitised.

What are the three ways GPCRs can become desensitized?

Receptor sequestration, down-regulation, and inactivation.

What family of kinases phosphorylates GPCRs leading to desensitization?

GPCR kinases (GRKs).

What do arrestins do in GPCR signaling?

Prevent interaction with G-proteins and help in endocytosis.

What does PKA stand for?

Protein Kinase A.

What does β2-adrenoceptor (β2AR) couple to?

Both Gαs and Gαi.

What additional pathway can β2AR signal through?

MAP kinase pathways through arrestin.

What are the efficacy classes of ligands?

Full agonists, partial agonists, neutral agonists, inverse agonists.

What is the role of olfactory receptors (ORs)?

Detect a diverse array of chemical structures.

What does the OR bind to in olfactory signaling?

Odour-ligand.

Which G-protein is activated by olfactory receptors?

Gαolf (a Gαs isoform enriched in OSNs).

What does Gαolf activate in olfactory neurons?

Adenylyl cyclase, leading to increased [cAMP].

What channels open due to increased cAMP in olfactory signaling?

Cyclic nucleotide gated (CNG) channels.

What subsequent effect does the influx of sodium and calcium ions cause in olfactory neurons?

Depolarization.

What is responsible for combining multiple signals in the olfactory system?

Combinatorial coding.

What happens when a single receptor recognises multiple odourants?

It activates different subsets of receptors.

How does the nose discriminate between different smells?

Using combinatorial coding.

What is important for the wiring of OSN axons in the olfactory bulb?

Olfactory receptors (ORs).

What does increased [cAMP] do to the expression of the axon guidance receptor?

It shifts innervation posteriorly.

What does decreased [cAMP] lead to in terms of axon innervation?

An anterior shift in innervation.

What is a key feature of receptor phosphorylation in GPCRs?

It regulates desensitization.

Which protein can act as an adaptor to help couple GPCRs to endocytosis?

Arrestins.

What effect do inverse agonists have on receptor activity?

Reduce basal or constitutive activity.

What role do GTPase activating proteins (GAPs) have?

They stimulate hydrolysis of GTP to GDP and inactivate GTP-binding proteins.