The tail of the gonadotrophin-releasing hormone receptor: desensitization at, and distal to, G protein-coupled receptors

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Abstract

In recent years a general scheme for the rapid desensitization and cycling of G protein-coupled receptors (GPCRs) has emerged. In this scheme agonist-induced phosphorylation (most often in the receptors’ C-terminal tail) causes association with β-arrestin which not only reduces the efficiency of G-protein activation, but also targets these desensitized receptors for internalization, after which they may be either proteolytically degraded or resensitized and recycled back to the cell surface. Although sustained stimulation of pituitary gonadotrophs with gonadotrophin-releasing hormone (GnRH) is known to cause a pronounced desensitization of GnRH-stimulated gonadotrophin secretion, the discovery that mammalian GnRH receptors do not possess C-terminal tails raised the question of whether receptor desensitization is involved. This review outlines data demonstrating that tail-less mammalian GnRH receptors can be considered as natural desensitization and internalization deficient ‘mutants’. This is in stark contrast to non-mammalian GnRH receptors which do possess tails and conform to the general scheme. In the absence of receptor desensitization, post receptor mechanisms take on increasing importance for desensitization of GnRH action via mammalian GnRH receptors. The down regulation of Ins(1,4,5)P3 receptors and consequent desensitization of GnRH effects on cytosolic Ca2+ are discussed as a novel mechanism for such desensitization.

Section snippets

Desensitization and cycling of GPCRs

G protein-coupled receptors (GCPRs), the largest known class of signaling proteins, are characterized structurally by the presence of seven trans-membrane domains, linked by a series of intracellular and extracellular loops. They mediate responses to a vast array of extracellular stimuli ranging from photons, amines, and lipids to peptides and proteins, and are currently major targets for therapeutic interventions. Following agonist binding, GPCRs act as guanine nucleotide exchange factors for

GnRH receptors and effectors

GnRH is a hypothalamic decapeptide which acts via GPCRs on gonadotrophs to stimulate the exocytotic secretion of luteinizing hormone and follicle-stimulating hormone. Agonist occupancy of GnRH receptors activates one or more isoforms of PLC, which hydrolyze membrane phosphoinositides. Hydrolysis of the minor membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) yields both diacylglycerol and Ins(1,4,5)P3 which activate most isoforms of protein kinase C (PKC) and mobilize

Do mammalian GnRH receptors undergo rapid homologous desensitization?

Although rapid receptor desensitization (through phosphorylation) is a generally accepted mechanism for GPCR regulation, it has proven technically difficult to demonstrate unambiguously that effects at the receptor level underlie desensitization of PLC-activating GPCRs (Wojcikiewicz et al., 1993) because factors other than receptor desensitization can influence the kinetics of [3H]IPx and Ins(1,4,5)P3 responses. Positive feedback effects of Ca2+ on PLC could conceivably lead to maintenance of

Is the lack of desensitization of mammalian GnRH receptors a result of the lack of required sites for phosphorylation in the C-terminal tail?

The obvious test for whether the lack of mammalian GnRH receptor desensitization is a result of the absence of a C-terminal tail would be to make chimeric receptors containing the GnRH receptor and the C-terminal tail of another GPCR. However, interpretation may be difficult as there is no guarantee that the added tail will adopt an appropriate structure and perform its appropriate function in this environment. It therefore created considerable interest when the first non-mammalian GnRH

What mechanisms of desensitization operate distal to the GnRH receptor?

It has long been known that GnRH-stimulated gonadotrophin secretion desensitizes during sustained stimulation of gonadotrophs with GnRH. The multiple mechanisms contributing towards this effect include depletion of intracellular gonadotrophin pools, internalization of GnRH receptors and GnRH receptor down-regulation. However, because these can be uncoupled from desensitization of gonadotrophin secretion (Jinnah and Conn, 1985, Jinnah and Conn, 1986, McArdle et al., 1987, Conn et al., 1987) and

Summary and directions

Mammalian GnRH receptors are unique. They are the smallest known GPCRs, the only PLC-coupled GPCRs known to lack C-terminal tails and the only PLC-activating GPCRs known not to undergo agonist-induced phosphorylation and desensitization. These features are in stark contrast to those of the non-mammalian GnRH receptors, and indeed to the vast majority of GPCRs including those of yeast. The implication is that these receptors have undergone a period of dramatically accelerated molecular evolution

Acknowledgements

This work was supported by Wellcome Trust (054949, 051555, 16895/1.5), the Neuroendocrine Charitable Trust (164,363) and the Special Trustees of the United of Bristol Hospital Trusts (947).

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