Since all 5-HT1 receptors couple to Gi–type G proteins and inhibit adenylyl cyclase, the functional significance of five distinct subtypes of 5-HT1 receptors has been unclear.
In previous studies we have used transfected cells to demonstrate that 5-HT1B receptors can couple more efficiently than 5-HT1A receptors to activation of extracellular signal-regulated kinase (ERK) and to inhibition of adenylyl cyclase. These findings suggested the possibility that individual 5-HT1 receptors differentially couple to isoforms of Giα.
In the present study we utilized a model system in which pertussis toxin resistant forms of human Giα1, Giα2, and Giα3 were used to directly compare the coupling of human 5-HT1A, 5-HT1B, and 5-HT1D receptors to each Giα in transfected human HeLa cells.
5-HT1A receptors displayed a preference for Giα1 and Giα2, relative to Giα3. Pertussis toxin resistant forms of Giα1, Giα2, and Giα3 rescued 73%, 76%, and 44%, respectively, of the ERK activation stimulated by 5-HT in the absence of pertussis toxin.
In contrast, pertussis toxin resistant forms of Giα1, Giα2, and Giα3 rescued 32%, 118%, and 35% of 5-HT1B receptor-stimulated activity, respectively, indicating that 5-HT1B receptors coupled primarily through Giα2. A similar preference for Giα2 was found in studies of the 5-HT1D receptor, where toxin resistant Giα1, Giα2, and Giα3 rescued 30%, 70%, and 40% of activity, respectively.
In conclusion, the observed differential coupling of 5-HT1 receptors to isoforms of Giα, provides additional evidence for our previous findings that the subtypes of 5-HT1 receptors exhibit similar, but distinct, functions.
British Journal of Pharmacology (2002) 136, 1072–1078. doi:10.1038/sj.bjp.0704809