Receptor-class desensitization

Huganir RL, Greengard P Regulation of neurotransmitter receptor desensitization by protein phosphorylation. Neuron 5 555-567, 1990 Hughes J, Boden P, Costall B, et al Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci U S A 87 6728-6732, 1990... 

Receptor desensitization may also be mediated by second-messenger feedback. For example, adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A protein kinase A can phosphorylate residues on receptors, resulting in inhibition of receptor function. For the B2 receptor, phosphorylation occurs on serine residues both in the third cytoplasmic loop and in the carboxyl terminal tail of the receptor. Similarly, activation of protein kinase C by Gq-coupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. This second-messenger feedback mechanism has been termed heterologous desensitization because activated protein kinase A or protein kinase C may phosphorylate any structurally similar receptor with the appropriate consensus sites for phosphorylation by these enzymes. 

An important concept to appreciate regarding receptors is that they are not static, stand-alone components of a cell. On the contrary, they are an integral part of the overall homeostatic balance of the body. For example, receptors can become desensitized upon continuous exposure to an agonist. When desensitization involves a specific class of agonists it is referred to as homologous desensitization. If response is reduced by disparate classes of drugs, the term heterologous desensitization is applied. 

Kainate receptors represent a third class of glutamate-gated ion channel, and are made up of subunits (GluR5-7, KAl and KA2) that are homologous to AMPA receptor subunits. The cytoplasmic domains of GluR6 and KA2 have been shown to bind to the PDZl domain and to the SH3 and GK domains of PSD-95, respectively (Garcia et al., 1998). Coexpression with PSD-95 can alter the desensitization properties of kainate receptors in heterologous expression systems. 

These act as agonists at NM receptors. They induce initial fasciculation, then paralysis, through desensitization of nicotinic acetylcholine receptors (Nn). Succinylcholine is a drug in this class. 

Used mainly in anesthesia protocols or in the ICU to afford muscle relaxation and/or immobility. Occasionally used to treat tetanus. These muscle relaxants interact with nicotinic receptors at the skeletal muscle end plate. Nicotinic receptors are comprised of five subunits, two of which (alpha) bind ACh, a requirement for opening of the Na+ channel. Most drugs in this class bind competitively to one of the alpha subunits to prevent depolarization (receptor antagonists) one drug (succinylcholine) binds noncompetitively and opens the Na+ channel, causing excessive depolarization and desensitization. 

Phosphorylation of the receptor by GRKs leads to creation of a high-affinity binding site for proteins known as arrestins. The family of arrestins includes the visual arrestins that are specific for rhodopsin and the /i-arrestins that bind, e.g., to the -adrenergic receptor. This class of -arrestins is most important for the desensitization of the activated receptor. Binding of /i-arrestins has several consequences ... 

This class of drugs desensitizes serotonergic receptors, as well as adrenergic receptors. This may account for the delayed onset of therapeutic effects, as upregulation of receptors may result. 

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