Novel brain-specific 5-HT4 receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain.

Abstract:

:We have cloned new 5-Hydroxytryptamine 4 (5-HT4) receptor splice variants from mouse (m5-HT4(e)R and m5-HT4(f)R), rat (r5-HT4(e)R), and human brain tissue (h5-HT4(e)R) which differ, as do the previously described 5-HT4 receptor variants, in the length and composition of their intracellular C termini after the common splicing site (L358). These new variants have a unique C-terminal sequence made of two PV repeats and are only expressed in brain tissue. All of the 5-HT4 receptor splice variants have a high constitutive activity when expressed at low and physiological densities (<500 fmol/mg protein). At similar density, they showed a much higher constitutive activity than the native and the mutated beta2-adrenergic receptors. The constitutive activity of the new splice variants with short C-terminal sequences (m5-HT4(e)R and m5-HT4(f)R) was higher than that of the long C-terminal sequence variants (m5-HT4(a)R and m5-HT4(b)R). This may indicate that the short variants have a higher capacity for isomerization from the inactive to the active conformation. Moreover, we further identified a sequence within the C-terminal tail upstream of L358, rich in serine and threonine residues, that played a crucial role in maintaining 5-HT4R under its inactive conformation.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Claeysen S,Sebben M,Becamel C,Bockaert J,Dumuis A

keywords:

subject

Has Abstract

pub_date

1999-05-01 00:00:00

pages

910-20

issue

5

eissn

0026-895X

issn

1521-0111

journal_volume

55

pub_type

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