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  • Title: Cell-specific physical and functional coupling of human 5-HT1A receptors to inhibitory G protein alpha-subunits and lack of coupling to Gs alpha.
    Author: Raymond JR, Olsen CL, Gettys TW.
    Journal: Biochemistry; 1993 Oct 19; 32(41):11064-73. PubMed ID: 8218170.
    Abstract:
    We have studied the physical and functional linkages of heterologously expressed human 5-HT1A receptors to G protein alpha-subunits in HeLa and CHO-K1 cells. HeLa cells expressed immunoreactivity to G(i) proteins with an apparent rank order of G(i) alpha 3 (approximately 1 pmol/mg of protein) >> G(i) alpha 1 (approximately 0.1 pmol/mg) >> G(i) alpha 2 (< 0.02 pmol/mg), whereas CHO-K1 cells expressed immunoreactivity to G(i) alpha 2 (approximately 5 pmol/mg) >> G(i) alpha 3 (approximately 0.7 pmol/mg), but not to G(i) alpha 1. Both cell lines expressed large and small forms of Gs alpha, but neither expressed detectable G(o) alpha. Agonist-promotable physical coupling of the 5-HT1A receptor to G proteins was examined with high-affinity agonist binding and with co-immunoprecipitation using rabbit anti-receptor IgG fractions. Agonist treatment induced coupling of the 5-HT1A receptors to G proteins with an apparent rank order of G(i) alpha 3 > G(i) alpha 1, G(i) alpha 2 in HeLa cells and G(i) alpha 3 > G(i) alpha 2 in CHO-K1 cells. Agonist-promotable functional coupling of the 5-HT1A receptors to inhibition of adenylylcyclase was measured in membranes derived from HeLa and CHO-K1 cells expressing approximately 2.5-3 pmol of receptors/mg of protein by preincubation with antisera raised against the carboxyl termini of the G(i) protein alpha-subunits. A noteworthy difference between the two cell types was that antisera against the predominant G protein (G(i) alpha 2) were substantially more efficacious than G(i) alpha 3 antisera at blocking functional coupling to adenylylcyclase inhibition in CHO-K1 cells, whereas in HeLa cells, antisera against nonpredominant G proteins (G(i) alpha 1/G(i) alpha 2) were equally as effective as those against the predominant G protein (G(i) alpha 3). No physical or functional coupling of the 5-HT1A receptor to Gs alpha isoforms was detected in either cell line. These findings suggest that the 5-HT1A receptor can physically couple to multiple distinct G(i) proteins in mammalian cell membranes and that functional coupling to adenylylcyclase inhibition may be mediated by G(i) alpha 1, G(i) alpha 2, and G(i) alpha 3. One factor influencing the relative importance of those G proteins for 5-HT1A receptor-inhibited adenylylcyclase activity appears to be their-relative levels of expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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