Molecular Determinants in the Second Intracellular Loop of the 5-Hydroxytryptamine-1A Receptor for G-Protein Coupling

2006 ◽  
Vol 69 (5) ◽  
pp. 1518-1526 ◽  
Author(s):  
Neena Kushwaha ◽  
Shannon C. Harwood ◽  
Ariel M. Wilson ◽  
Miles Berger ◽  
Laurence H. Tecott ◽  
...  
Keyword(s):  
G Protein ◽  
Intracellular Loop ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Molecular Determinants

scholarly journals Intracellular Loop 2 Peptides of the Human 5HT1a Receptor are Differential Activators of Gi

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Brian Hall ◽  
Carley Squires ◽  
Keith K. Parker
Keyword(s):  
G Protein ◽  
Pharmacological Intervention ◽  
Intracellular Camp ◽  
Intracellular Loop ◽  
Peptide Mimics ◽  
G Protein Coupling ◽  
5Ht1a Receptor ◽  
Protein Coupling ◽  
Loop Region ◽  
Loop 2

Peptide mimics of intracellular loop 2 (ic2) of the human 5HT1a receptor have been studied with respect to their ability to inhibit agonist binding via interference with receptor-G-protein coupling. These peptides give shallow concentration-effect relationships. Additionally, these peptides have been studied with respect to their ability to trigger the signal transduction system of this Gi-coupled receptor. Two signaling parameters have been quantified: concentration of intracellular cAMP and changes in incorporation into the G protein of a stable analog of GTP. In both cases, peptide mimics near midloop of ic2 actually show agonist activity with efficacy falling off toward both loop termini near TM 3 and TM 4. Previous results have suggested that the loop region near the TM3/ic2 interface is primarily responsible for receptor-G-protein coupling, while the current result emphasizes the mid-ic2 loop region's ability to activate the G protein following initial coupling. A limited number of peptides from the receptor's TM5/ic3 loop vicinity were also studied regarding agonist inhibition and G-protein activation. These peptides provide additional evidence that the human 5HT1a receptor, TM5/ic3 loop region, is involved in both coupling and activation actions. Overall, these results provide further information about potential pharmacological intervention and drug development with respect to the human 5HT1a receptor/G-protein system. Finally, the structural evidence generated here provides testable models pending crystallization and X-ray analysis of the receptor.

scholarly journals The allosteric enhancer PD81,723 increases chimaeric A1/A2A adenosine receptor coupling with Gs

2006 ◽  
Vol 396 (1) ◽  
pp. 139-146 ◽  
Author(s):  
Samita Bhattacharya ◽  
Rebecca L. Youkey ◽  
Kobina Ghartey ◽  
Matthew Leonard ◽  
Joel Linden ◽  
...  
Keyword(s):  
G Protein ◽  
Adenosine Receptor ◽  
Intracellular Loop ◽  
Dissociation Kinetics ◽  
A2a Adenosine Receptor ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Receptor Coupling ◽  
A1 Receptor ◽  
Coupling Specificity

PD81,723 {(2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluromethyl)-phenyl]methanone} is a selective allosteric enhancer of the Gi-coupled A1 AR (adenosine receptor) that is without effect on Gs-coupled A2A ARs. PD81,723 elicits a decrease in the dissociation kinetics of A1 AR agonist radioligands and an increase in functional agonist potency. In the present study, we sought to determine whether enhancer sensitivity is dependent on coupling domains or G-protein specificity of the A1 AR. Using six chimaeric A1/A2A ARs, we show that the allosteric effect of PD81,723 is maintained in a chimaera in which the predominant G-protein-coupling domain of the A1 receptor, the 3ICL (third intracellular loop), is replaced with A2A sequence. These chimaeric receptors are dually coupled with Gs and Gi, and PD81,723 increases the potency of N6-cyclopentyladenosine to augment cAMP accumulation with or without pretreatment of cells with pertussis toxin. Thus PD81,723 has similar functional effects on chimaeric receptors with A1 transmembrane sequences that couple with Gi or Gs. This is the first demonstration that an allosteric regulator can function in the context of a switch in G-protein-coupling specificity. There is no enhancement by PD81,723 of Gi-coupled A2A chimaeric receptors with A1 sequence replacing A2A sequence in the 3ICL. The results suggest that the recognition site for PD81,723 is on the A1 receptor and that the enhancer acts to directly stabilize the receptor to a conformational state capable of coupling with Gi or Gs.

scholarly journals Amino acid residues in third intracellular loop of melanocortin 1 receptor are involved in G-protein coupling

IUBMB Life ◽  
1998 ◽  
Vol 46 (5) ◽  
pp. 913-922
Author(s):  
Per-Anders Frändberg ◽  
Marina Doufexis ◽  
Supriya Kapas ◽  
Vijay Chhajlani
Keyword(s):  
Amino Acid ◽  
G Protein ◽  
Amino Acid Residues ◽  
Intracellular Loop ◽  
G Protein Coupling ◽  
Melanocortin 1 Receptor ◽  
Protein Coupling ◽  
Third Intracellular Loop
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