A NATURALLY-OCCURRING AMINO-ACID SUBSTITUTION OF THE HUMAN SEROTONIN 5-HT2A RECEPTOR INFLUENCES AMPLITUDE AND TIMING OF INTRACELLULAR CALCIUM MOBILIZATION

Recently, two naturally occurring amino acid substitutions were identi fied in the C-terminal region of the serotonin 5-HT2A receptor. One of these, His(452)Tyr, has a rarer allele Tyr frequency of 9%. If (452)T yr alters 5-HT2A function, it would thus be a candidate allele for hum an neurobehavioral variation. The present study was designed to evalua te the potential influence of the (452)His and (452)Tyr alleles on cel lular 5-HT2A functions. Platelet 5-HT2A binding and 5-HT-induced Ca2response were compared in eight (452)His/(452)His homozygous and eight (452)His/(452)Tyr heterotygous individuals matched for sex, age, and diagnosis (all were patients with seasonal affective disorder). There was no difference in 5-HT2A binding measured using I-125-lysergic acid diethylamide, Nor were levels of G-protein subunits or PKC alpha, del ta, epsilon, or zeta significantly altered. However, when Ca2+ respons e was stimulated by 2, 5, 10, or 25 mu M 5-HT, significant differences were found. In (452)His/(452)Tyr heterozygotes, (452)Tyr was associat ed with both smaller peak amplitude in Ca2+ mobilization and a differe nt time course of response, with slower peak latency and longer half-t ime in (452)His/(452)Tyr heterozygotes compared with (452)His/(452)His homozygotes. The overall difference in the response of the 5-HT2A rec eptor in individuals with (452)Tyr was a blunting of the shape of the Ca2+ mobilization peak. The data reported here suggest that the primar y sequence of this intracellular domain is important in function of th e receptor and that the (452)His and (452)Tyr 5-HT2A alleles should be carefully evaluated for effects on human neurobehavioral variation.