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Genetic Variation in Human 5‐HT Receptors: Potential Pathogenetic and Pharmacological Role a
Author(s) -
GÖTHERT M.,
PROPPING P.,
BÖNISCH H.,
BRÜSS M.,
NÖTHEN M. M.
Publication year - 1998
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1998.tb10169.x
Subject(s) - receptor , 5 ht receptor , serotonin , chemistry , radioligand , medicine , radioligand assay , endocrinology , biology , biochemistry
Mutation screening identified variants of h5‐HT 1A (Gly‐22‐Ser, Ile‐28‐Val, Arg‐219‐Leu), h5‐HT 1B (Phe‐124‐Cys), h5‐HT 2A (Thr‐25‐Asn, His‐452‐Tyr), h5‐HT 2C (Cys‐23‐Ser) and h5‐HT 7 (Thr‐92‐Lys, Pro‐279‐Leu) receptors. Screening of h5‐HT 1D , h5‐ht 1e , h5‐ht 1f and h5‐ht 5 receptor genes failed to detect any significant mutations. No differences in radioligand binding properties were observed between the h5‐HT 1A Ile‐28‐Val variant receptor (VR) and the wildtype receptor (WTR). Binding profiles of the h5‐HT 1A Gly‐22‐Val variant and the WTR were also very similar, but the 8‐OH‐DPAT‐induced down‐regulation and desensitization of the VR was attenuated. The h5‐HT 1B Phe‐124‐Cys variant leads to considerable changes in [ 3 H]5‐carboxamidotryptamine binding: B max was decreased and the affinity of various h5‐HT 1B ligands was modified (usually increased; e.g. , in the case of sumatriptan). The h5‐HT 2A His‐452‐Tyr variant causes an alteration of the amplitude and timing of intracellular calcium mobilization in platelets from 452‐His/452‐Tyr heterozygous compared to 452‐His/452‐His homozygous individuals. Most, but not all, of the VRs listed above were examined for association with, e.g. , bipolar depression and schizoprenia, yet no relation was observed. The most consistent finding was an association between a silent mutation (102T/C) in the h5‐HT 2A receptor gene and schizophrenia; this association may be explained by linkage disequilibrium with a functional variant in the regulatory region of the gene. Studies of the therapeutic response to clozapine produced no homogeneous results with respect to the pharmacogenetic significance of the various mutations in the h5‐HT 2A and h5‐HT 2C receptor genes.