Impairment of signal transduction in response to stimulation of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor.

Abstract

The aim of this study, performed in stably transfected HEK293 cells, was to investigate whether expression of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor (located in the third intracellular loop) is associated with changes in the pharmacological properties and/or second messenger formation compared to the wild-type receptor. Radioligand binding of [3H]5-carboxamidotryptamine ([3H]5-CT) to membranes and stimulation of [3H]cAMP formation in whole cells evoked by 5-HT receptor agonists were determined. Maximum binding (B(max)) to, and affinity (K(D)) of [3H]5-CT for, the variant receptor and the wild-type receptor were equal. All agonists and antagonists investigated exhibited no differences in affinity between the variant receptor and the wild-type receptor. However, the intrinsic activity of the 5-HT receptor agonists 5-HT, 5-CT, RU24969 and 8-OH-DPAT in stimulating [3H]cAMP accumulation in the cells expressing the Pro279Leu variant was almost abolished and their potency was 2.9-4.3-fold lower. Despite its affinity for both receptor isoforms, sumatriptan did not stimulate the accumulation of cAMP. In individuals expressing the Pro279Leu variant of the h5-HT7(a) receptor, a considerable attenuation of its function may be predicted. This may have relevance for the action of new classes of drugs which affect circadian rhythm or psychiatric diseases, such as schizophrenia.