Differential coupling of 5-HT 1 receptors to G proteins of the G i family

Abstract

1. Since all 5-HT 1 receptors couple to G i-type G proteins and inhibit adenylyl cyclase, the functional significance of five distinct subtypes of 5-HT 1 receptors has been unclear. 2. In previous studies we have used transfected cells to demonstrate that 5-HT 1B receptors can couple more efficiently than 5-HT 1A receptors to activation of extracellular signal-regulated kinase (ERK) and to inhibition of adenylyl cyclase. These findings suggested the possibility that individual 5-HT 1 receptors differentially couple to isoforms of G iα. 3. In the present study we utilized a model system in which pertussis toxin resistant forms of human G iα1, G iα2, and G iα3 were used to directly compare the coupling of human 5-HT 1A, 5-HT 1B, and 5-HT 1D receptors to each G iα in transfected human HeLa cells. 4. 5-HT 1A receptors displayed a preference for G iα1 and G iα2, relative to G iα3. Pertussis toxin resistant forms of G iα1, G iα2, and G iα3 rescued 73%, 76%, and 44%, respectively, of the ERK activation stimulated by 5-HT in the absence of pertussis toxin. 5. In contrast, pertussis toxin resistant forms of G iα1, G iα2, and G iα3 rescued 32%, 118%, and 35% of 5-HT 1B receptor-stimulated activity, respectively, indicating that 5-HT 1B receptors coupled primarily through G iα2. A similar preference for G iα2 was found in studies of the 5-HT 1D receptor, where toxin resistant G iα1, G iα2, and G iα3 rescued 30%, 70%, and 40% of activity, respectively. 6. In conclusion, the observed differential coupling of 5-HT 1 receptors to isoforms of G iα, provides additional evidence for our previous findings that the subtypes of 5-HT 1 receptors exhibit similar, but distinct, functions.