Agonist-Promoted Down-Regulation and Functional Desensitization in Two Naturally Occurring Variants of the Human Serotonin1A Receptor

Abstract

We recently reported two naturally occurring polymorphisms of the human serotonin 1A receptor: glycine22 → serine (Ser22) and isoleucine28 → valine (Val28) (Kobilka et al. 1987;Chanda et al. 1993) coded by an intronless gene located on chromosome 5 at 5q11.2-q13 (Kobilka et al. 1987). Like other members of the G-protein-coupled receptor family (Dohlman et al. 1991), the 5-HT 1A receptor consists of seven transmembrane hydrophobic domains, with an extracellular aminoterminal domain and a cytoplasmic carboxyl-terminus. By coupling with the G i/o family of heterotrimeric G proteins, the 5-HT 1A receptor has been shown to either inhibit or activate adenylate cyclase activity, open potassium channels, close calcium channels, and inhibit phosphatidylinositol turnover (reviewed in Boess and Martin 1994). The 5-HT 1A receptor is expressed both presynaptically on the cell bodies and the dendrites of serotonergic neurons located in the raphe nuclei and postsynaptically with the highest density in the limbic system (Zifa and Fillon 1992;Burnet et al. 1995).The 5-HT 1A receptor is believed to play a role in a variety of behaviors, such as aggression, sexual behavior, and appetite control, and in several psychiatric disorders, such as mood disorders, anxiety disorders, anorexia ner-

Agonist- and antagonist-induced plasticity of rat 5-HT1A receptor in hippocampal cell culture

“…These results are consistent with the mechanisms involving downregulation of the 5-HT 1A receptor by agonists and normalization of the 5-HT 1A receptor by antagonists at the protein expression level. Recent in vitro study also demonstrated that agonist promoted downregulation and functional desensitization in naturally occurring variants of the human 5-HT 1A receptor (Rotondo et al, 1997). Our results are consistent with reports in adult animals that decreased serotonin levels result in an increase in the following parameters: 5-HT 1A receptor protein expression (Patel et al, 1996), agonist binding (Nelson et al, 1978;Morrow et al, 1985;Blurton and Wood, 1986;Frankfurt et al, 1993Frankfurt et al, , 1994, and functional sensitivity (Azmitia et al, 1978;Blackburn et al, 1984;Nabeshima et al, 1987;Engleman et al, 1991).…”

“…In contrast, receptor upregulation occurs in response to conditions that prevent receptors from being activated. However, it has been suggested that 5-HT 1A receptor expression is regulated in an anomalous manner, with no consistent compensatory changes in response to agonists, antagonists, or serotonin denervation (Morrow et al, 1985;Blurton and Wood, 1986;Verge et al, 1986;Frazer and Hensler, 1990;Hensler et al, 1991;Miquel et al, 1992;Frankfurt et al, 1993Frankfurt et al, , 1994Patel et al, 1996;Rotondo et al, 1997). A compounding factor is that adrenal steroids have been shown to downregulate the 5-HT 1A receptor mRNA (Chalmers et al, 1993;Meijer and deKloet, 1994).…”

Variability in the Benzodiazepine Response of Serotonin 5-HT1AReceptor Null Mice Displaying Anxiety-Like Phenotype: Evidence for Genetic Modifiers in the 5-HT-Mediated Regulation of GABAAReceptors

“…Diminished 5-HT 1A R signaling could be attributable to lower expression but also to structural receptor polymorphism. At least four structural variants of the 5-HT 1A receptor have been described that affect various domains of the receptor, including the first transmembrane domain, second intracellular loop, and third intracellular loop that is involved in G-protein binding (Rotondo et al, 1997;Kawanishi et al, 1998).…”

A Tryptophan Hydroxylase Gene Marker for Suicidality and Alcoholism

“…Several serotonergic variants alter the expression or the properties of the gene product and may modify behavior. A 5-HT 1A variant lowers agonist-mediated receptor down-regulation rate and desensitization, 21 and a 5-HT 2A variant diminishes serotonin-mediated intracellular calcium release. 27 In 1 kindred, a monoamine oxidase A variant produced a truncated protein that led to an X-linked syndrome characterized by increased impulsive behavior.…”