Question

Rationalise the concept of multiple receptor states for G protein coupled receptors and how this might be used to develop novel and more selective drugs.

Answer 1

G protein coupled receptors (GPCR) are a huge transmembrane receptor protein family which are able to respond to a variety of extracellular stimulus such as photons, small molecules, peptides and proteins (hormones, neurotransmitters and paracrine agents). The contact of these receptors with its ligands will promote several transduction signals and finally a specific cellular response. In human, these receptors are involved in several neurological, cardiovascular, endocrine and reproductive functions. This ubiquity make GPCR the main target to develop drugs treatments (around 40% of modern drugs are targeted to GPCR).

Depending on the G protein coupled receptor and It ligands, drugs has been synthesized to mimic or block signals for these receptors, making a selective treatment for patients. But how this works? The receptors are able to bind to Its ligands on the extracellular side leading to the activation by the ligand (or drug). This will cause a conformational change leading to the intracellular loops to bind and activate the G protein. Once, the G-protein is activated, It will dissociate from the receptor and its subunits will activate a second messenger response activating or inhibiting other effector molecules (for example phospholipases or enzymes)