Abstract
The molecular basis of selectivity in G-protein receptor coupling has been explored by comparing the abilities of G-protein heterotrimers containing chimeric Galpha subunits, comprised of various regions of Gi1alpha, Gtalpha, and Gqalpha, to stabilize the high affinity agonist binding state of serotonin, adenosine, and muscarinic receptors. The data indicate that multiple and distinct determinants of selectivity exist for individual receptors. While the A1 adenosine receptor does not distinguish between Gi1alpha and Gtalpha sequences, the 5-HT1A and 5-HT1B serotonin and M2 muscarinic receptors can couple with Gi1 but not Gt. It is possible to distinguish domains that eliminate coupling and are defined as "critical," from those that impair coupling and are defined as "important." Domains within the N terminus, alpha4-helix, and alpha4-helix-alpha4/beta6-loop of Gi1alpha are involved in 5-HT and M2 receptor interactions. Chimeric Gi1alpha/Gqalpha subunits verify the critical role of the Galpha C terminus in receptor coupling, however, the individual receptors differ in the C-terminal amino acids required for coupling. Furthermore, the EC50 for interactions with Gi1 differ among the individual receptors. These results suggest that coupling selectivity ultimately involves subtle and cooperative interactions among various domains on both the G-protein and the associated receptor as well as the G-protein concentration.
Highlights
A large number of diverse seven transmembrane-spanning cell surface receptors mediate signaling to a variety of intracellular effectors by coupling to the heterotrimeric guanine nucleotide-binding regulatory proteins (G-proteins)1 [1]
Chimeric Gi1␣/Gq␣ subunits verify the critical role of the G␣ C terminus in receptor coupling, the individual receptors differ in the C-terminal amino acids required for coupling
We propose that individual receptors recognize specific patterns formed by amino acids of G␣ making G-protein interface look different for different receptors
Summary
A large number of diverse seven transmembrane-spanning cell surface receptors mediate signaling to a variety of intracellular effectors by coupling to the heterotrimeric guanine nucleotide-binding regulatory proteins (G-proteins)1 [1]. Of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 Both receptor and G-protein, the individual amino acids involved in this selective recognition have not been completely identified. Different receptor systems and different methodologies indicate that the G␣ subunit C terminus and ␣5-helix (4 –7), N terminus, and ␣N-helix (4, 8 –10), ␣4-helix, and ␣4/ 6-loop [11,12,13], ␣2-helix, and ␣2/4-loop [14], ␣3/5-loop [15], ␣N/1-loop [13] and amino acids 110 –119 from the ␣-helical domain [16] are involved in receptor-coupling selectivity. Demonstrated that 5-HT1A and 5-HT1B receptors distinguish themselves by the affinity with which they interact with G-
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