G – protein coupled receptors

These are also known as metabotropic receptors or 7-trans-membrane spanning receptors. They are membrane receptors which are coupled to intracellular effector systems via a G protein.

G- proteins and the role of G- proteins

These were called as G proteins because of the interaction with the guanine nucleotides, GTP and GDP.

G –proteins consist of 3 sub unite α, β and γ. Guanine nucleotides bind to the α sub unite which has enzymatic activity catalysing the conversion of GTP to GDP. The β, γ subunits remain associated as βγ complex. All 3 subunits are anchored to the membrane through a fatty acid chain. G – proteins appear to be freely diffusible in the plane of the membrane.

In the resting state, the G- protein exists as an unattached αβγ trimer, with GDP occupying the site on the α subunit. When a receptor is occupied by an agonist molecule, a conformational change occurs, involving the cytoplasmic domain of the receptor causing it to acquire high affinity for αβγ.

Association of αβγ with the receptor causes the bound GDP to dissociate and to be replaced with GTP [GDP/GTP exchange], which in turn causes dissociation of the G – protein trimer, releasing α-GTP and βγ subunits; these are the “active” forms of the G-protein, which diffuse in the membrane and can associate with various enzymes and ion channels, causing activation or inactivation. The process is terminated when the hydrolysis of GTP to GDP occurs through the GTPase activity of the α-subunit. The resulting α-GDP then dissociates from the effector and reunites with βγ, completing the scale.

Targets for G – proteins are

a) The adenylate cyclise or cAMP system

b) Phospholipase system

Regulation of ion channels:

G – protein coupled receptors can control ion channel function by mechanisms that do not involve any second messengers such as cAMP or inositol phosphates. In cardiac muscle, for eg., muscarinic ACh receptors are known to enhance potassium permeability(thus hyperpolarising the cells and inhibiting electrical activity).

Excellent animated explanation of the same can be viewed on http://sitemaker.umich.edu/maybaum.pharmacology.principles/g-protein

References:

• Picture taken from http://www.nature.com/nrc/journal/v7/n2/images/nrc2069-f1.jpg

• Pharmacology by H.P.Rang, M.M.Dale and J.M.Ritter.

• Essentials of Medical Pharmacology by K.D.Tripathi