GPCRs efficacy

Question 1

What is a receptor reserve and how does it affect results

Answer 1

Where there are excess receptors, meaning that not all the receptors on the cell surface need to be activated to get a 100% response. Increasing dose beyond this level would not increase signalling even if more receptors were activated.

Can make drugs appear to have altered potency and affinity. A partial agonist may elicit a maximal response when there is a receptor reserve.

Question 2

What is signal amplification

Answer 2

When signalling occurs through a GPCR, what is being measured in the assay makes a big impact. If a downstream messenger is being measured, it can be subject to signal amplification, which would make it appear to have a stronger response.

Here, a maximal downstream response may not be elicited by full receptor occupancy.

This is another mechanism through which maximal signalling can occur even though there is not 100% occupancy of the receptors.

Question 3

What factors does potency and Emax depend on

Answer 3

Drug factors: efficacy and affinity

System factors: receptor numbers and efficiency of coupling (with signalling molecules)

All of these play a role in the potency of a drug.

Affinity does not play a role in the Emax of a drug however.

Question 4

What is an operational model of agonism and what unit is used to describe it

Answer 4

Tau is the intrinsic efficacy of a drug, accounting for the sensitivity of the assay’s system.

Tau = [RT]/KE
where RT = [receptors] and KE = the equilibrium dissociation constant of the agonist-receptor-signalling molecule complex - takes into account agonist efficacy and signal amplification.

There is a full equation for attaining this value, and it can be turned into a Hill slope.

Question 5

What is represented by different values of Tau

Answer 5

As Tau gets smaller, the logEC50 approximates LogKA

The larger the Tau value, the more potent it is.

As Tau gets larger, the more difference there is between affinity and potency.

Question 6

Method used to approximate LogKA and agonist effects

Answer 6

As the smaller the Tau gets, the closer the LogEC50 resembles the LogKA of the drug, irreversible antagonists have been used as a method for this.

Alkylating receptors using an irreversible antagonists reduces the [RT], while not affecting the affinity or emax of the ligand, nor the slope of the curve.

Using ratios of KA and Tau can be used as a predictive tool for the effect of agonists in different tissues.