Differential coupling of 5-HT1 receptors to G proteins of the Gi family

Authors

  • Stanley L Lin,

    1. Department of Psychiatry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey, NJ 08901, U.S.A.
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  • Shilpy Setya,

    1. Department of Psychiatry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey, NJ 08901, U.S.A.
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  • Nadine N Johnson-Farley,

    1. Department of Psychiatry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey, NJ 08901, U.S.A.
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  • Daniel S Cowen

    Corresponding author
    1. Department of Psychiatry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey, NJ 08901, U.S.A.
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Department of Psychiatry, UMDNJ–Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, New Jersey, NJ 08901, USA. E-mail: cowends@umdnj.edu

Abstract

  • 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 G.

  • 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 G 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 G, 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

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