What are receptors?

A receptor is defined as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes, nucleic acids, and structural proteins can act as receptors for drugs or endogenous agonists.

These receptors may be divided into four families:

G protein–coupled receptors,
Ligand-gated ion channels,
Enzyme-linked receptors, and
Intracellular receptors.

Generally, hydrophilic ligands interact with receptors that are found on the cell surface. In contrast, hydrophobic ligands enter cells through the lipid bilayers of the cell membrane to interact with receptors found inside cells.

G-protein coupled receptors (GPCRs)

Diagrammatic representation of G-protein coupled receptor molecule

The receptor consists of 7 membrane spanning helical segments of hydrophobic amino acids. The intervening segments connecting the helices form 3 loops on either side of the membrane. The amino terminus of the chain lies on the extracellular face, while the carboxy terminus is on the cytosolic side. The approximate location of the agonist and G-protein binding sites is indicated.

These are a large family of cell membrane receptors which are linked to the effector (enzyme/channel/transporter) through one or more GTP-activated proteins (G-proteins) for response effectuation. All such receptors have a common pattern of structural organization. The molecule has 7 α-helical membrane spanning hydrophobic amino acid (AA) segments which run into 3 extracellular and 3 intracellular loops. The agonist binding site is located somewhere between the helices on the extracellular face, while another recognition site formed by cytosolic segments binds the coupling G-protein.

The G-proteins float in the membrane with their exposed domain lying in the cytosol, and are heterotrimeric in composition (α, β and γ subunits). In the inactive state GDP is bound to the α subunit at the exposed domain; activation through the receptor leads to displacement of GDP by GTP. The activated α-subunit carrying GTP dissociates from the other two subunits and either activates or inhibits the effector. The βγ diamer has also been shown to activate receptor-operated K+ channels, to inhibit voltage gated Ca2+ channels and to promote GPCR desensitization at higher rates of activation.

The recognition of chemical signals by G protein–coupled membrane receptors affects the activity of adenylyl cyclase. PPi =inorganic pyrophosphate.

A number of G proteins distinguished by their α subunits have been described. The important ones with their action on the effector are:

🔹Gs : Adenylyl cyclase activation, Ca2+ channel opening

🔹Gi : Adenylyl cyclase inhibition, K+ channel opening

🔹Go : Ca2+ channel inhibition

🔹Gq : Phospholipase C activation

A limited number of G-proteins are shared between different receptors and one receptor can utilize more than one G-protein (agonist pleotropy), e.g. the following couplers have been associated with different receptors.

In addition, Gs is the coupler for histamine H2, serotonin 5HT4-7, glucagon, thyrotropin (TSH) and many other hormones, while Gi is utilized by opioid, cannabinoid and some other receptors. Moreover, a receptor can utilize different biochemical pathways in different tissues.

The α-subunit has GTPase activity: the bound GTP is slowly hydrolysed to GDP: the α-subunit then dissociates from the effector to rejoin its other subunits, but not before the effector has been activated/ inhibited for several seconds (much longer than the life-time of the activated receptor, which is in milliseconds) and the signal has been greatly amplified. The rate of GTP hydrolysis by the α subunit and thus the period for which it remains activated is regulated by another protein called‘regulator of G protein signaling’ (RGS). The onset time of response through GPCRs is in seconds.

There are three major effector pathways through which GPCRs function

a) Adenylyl cyclase: cAMP pathway

b) Phospholipase C: IP3-DAG pathway

c) Channel regulation

A common effector, activated by Gs and inhibited by Gi, is adenylyl cyclase, which produces the second messenger cyclic adenosine monophosphate (cAMP). The effector phospholipase C, when activated by Gq, generates two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). DAG and cAMP activate specific protein kinases within the cell, leading to a myriad of physiological effects. IP3 increases intracellular calcium concentration, which in turn activates other protein kinases.

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