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 identified in the C-terminal region of the serotonin 5-HT2A receptor. One of these, His452Tyr, has a rarer allele Tyr frequency of 9%. If 452Tyr alters 5-HT2A function, it would thus be a candidate allele for human neurobehavioral variation. The present study was designed to evaluate the potential influence of the 452His and 452Tyr alleles on cellular 5-HT2A functions. Platelet 5-HT2A binding and 5-HT-induced Ca2+ response were compared in eight 452His/452His homozygous and eight 452His/452Tyr heterozygous individuals matched for sex, age, and diagnosis (all were patients with seasonal affective disorder). There was no difference in 5-HT2A binding measured using 125I-lysergic acid diethylamide. Nor were levels of G-protein subunits or PKC alpha, delta, epsilon, or zeta significantly altered. However, when Ca2+ response was stimulated by 2, 5, 10, or 25 microM 5-HT, significant differences were found. In 452His/452Tyr heterozygotes, 452Tyr was associated with both smaller peak amplitude in Ca2+ mobilization and a different time course of response, with slower peak latency and longer half-time in 452His/452Tyr heterozygotes compared with 452His/452His homozygotes. The overall difference in the response of the 5-HT2A receptor in individuals with 452Tyr was a blunting of the shape of the Ca2+ 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 452His and 452Tyr 5-HT2A alleles should be carefully evaluated for effects on human neurobehavioral variation.
Ozaki
N
N
Clinical Psychobiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, U.S.A.
Manji
H
H
Lubierman
V
V
Lu
S J
SJ
Lappalainen
J
J
Rosenthal
N E
NE
Goldman
D
D
D000328:Adult; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008238:Lysergic Acid Diethylamide / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D011493:Protein Kinase C / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics* / Q000502:physiology*; D013997:Time Factors
D007527:Isoenzymes; D011985:Receptors, Serotonin; D008238:Lysergic Acid Diethylamide; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D002118:Calcium