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A Naturally Occurring Amino Acid Substitution of the Human Serotonin 5‐HT 2A Receptor Influences Amplitude and Timing of Intracellular Calcium Mobilization
Author(s) -
Ozaki Norio,
Manji Husseini,
Lubierman Victoria,
Lu Sha Jia,
Lappalainen Jaakko,
Rosenthal Norman E.,
Goldman David
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68052186.x
Subject(s) - serotonin , allele , medicine , endocrinology , receptor , 5 ht receptor , amino acid , heterozygote advantage , calcium , biology , biochemistry , gene
Recently, two naturally occurring amino acid substitutions were identified in the C‐terminal region of the serotonin 5‐HT 2A receptor. One of these, His 452 Tyr, has a rarer allele Tyr frequency of 9%. If 452 Tyr alters 5‐HT 2A function, it would thus be a candidate allele for human neurobehavioral variation. The present study was designed to evaluate the potential influence of the 452 His and 452 Tyr alleles on cellular 5‐HT 2A functions. Platelet 5‐HT 2A binding and 5‐HT‐induced Ca 2+ response were compared in eight 452 His/ 452 His homozygous and eight 452 His/ 452 Tyr heterozygous individuals matched for sex, age, and diagnosis (all were patients with seasonal affective disorder). There was no difference in 5‐HT 2A binding measured using 125 I‐lysergic acid diethylamide. Nor were levels of G‐protein subunits or PKC α, δ, ε, or ζ significantly altered. However, when Ca 2+ response was stimulated by 2, 5, 10, or 25 µ M 5‐HT, significant differences were found. In 452 His/ 452 Tyr heterozygotes, 452 Tyr was associated with both smaller peak amplitude in Ca 2+ mobilization and a different time course of response, with slower peak latency and longer half‐time in 452 His/ 452 Tyr heterozygotes compared with 452 His/ 452 His homozygotes. The overall difference in the response of the 5‐HT 2A receptor in individuals with 452 Tyr was a blunting of the shape of the Ca 2+ mobilization peak. The data reported here suggest that the primary sequence of this intracellular domain is important in function of the receptor and that the 452 His and 452 Tyr 5‐HT 2A alleles should be carefully evaluated for effects on human neurobehavioral variation.