Abstract

We have cloned new 5-Hydroxytryptamine 4 (5-HT₄) receptor splice variants from mouse (m5-HT_4(e)R and m5-HT_4(f)R), rat (r5-HT_4(e)R), and human brain tissue (h5-HT_4(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 β₂-adrenergic receptors. The constitutive activity of the new splice variants with short C-terminal sequences (m5-HT_4(e)R and m5-HT_4(f)R) was higher than that of the long C-terminal sequence variants (m5-HT_4(a)R and m5-HT_4(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.