TY - JOUR T1 - Novel Brain-Specific 5-HT<sub>4</sub> Receptor Splice Variants Show Marked Constitutive Activity: Role of the C-Terminal Intracellular Domain JF - Molecular Pharmacology JO - Mol Pharmacol SP - 910 LP - 920 VL - 55 IS - 5 AU - Sylvie Claeysen AU - Michèle Sebben AU - Carine Becamel AU - Joël Bockaert AU - Aline Dumuis Y1 - 1999/05/01 UR - http://molpharm.aspetjournals.org/content/55/5/910.abstract N2 - 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 (&lt;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-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. The American Society for Pharmacology and Experimental Therapeutics ER -