RT Journal Article
SR Electronic
T1 Allosterism within delta opioid-kappa opioid receptor heteromers in peripheral sensory neurons: Regulation of kappa opioid agonist efficacy
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.117.109975
DO 10.1124/mol.117.109975
A1 Blaine Jacobs
A1 Miryam M Pando
A1 Elaine M Jennings
A1 Teresa S Chavera
A1 William P Clarke
A1 Kelly A. Berg
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/02/07/mol.117.109975.abstract
AB There is abundant evidence for formation of G protein coupled receptor heteromers in heterologous expression systems, however, little is known of the function of heteromers in native systems. Heteromers of delta and kappa opioid receptors (DOR-KOR heteromers) have been identified in native systems. We previously reported that activation of DOR-KOR heteromers expressed by rat pain-sensing neurons (nociceptors) produces robust, peripherally-mediated antinociception. Moreover, DOR agonist potency and efficacy is regulated by KOR antagonists via allosteric interactions within the DOR-KOR heteromer in a ligand-dependent manner. Here we assessed the reciprocal regulation of KOR agonist function by DOR antagonists in adult rat nociceptors in culture and in a behavioral assay of nociception. Naltrindole enhanced the potency of the KOR agonist ICI-199441 (10-20 fold), but did not alter responses to U50488. By contrast, the potency of U50488 was enhanced (20 fold) by 7-benzylidenenaltrexone. The efficacy of 6'-guanidinonaltrindole (6'-GNTI) to inhibit nociceptors was blocked by siRNA knock-down of DOR or KOR. Replacing 6'-GNTI occupancy of DOR with either naltrindole or 7-benzylidenenaltrexone abolished 6'-GNTI efficacy. Further, peptides derived from DOR transmembrane segment 1, fused to the cell membrane penetrating HIV transactivator of transcription peptide, also blocked 6'-GNTI-mediated responses ex vivo and in vivo, suggesting that 6'-GNTI efficacy in nociceptors is due to its positive allosteric regulation of KOR via occupancy of DOR in a DOR-KOR heteromer. Together, these results provide evidence for the existence of functional DOR-KOR heteromers in rat peripheral sensory neurons and that reciprocal, ligand-dependent, allosteric interactions occur between the DOR and KOR protomers.