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The Journal of Neuroscience, April 7, 2004, 24(14):3663-3671; doi:10.1523/JNEUROSCI.4773-03.2004
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Cellular/Molecular
Direct Interaction of Adenosine with the TRPV1 Channel Protein
Preeti Puntambekar, Jeremy Van Buren, Manish Raisinghani, Louis S. Premkumar, andVickram Ramkumar Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9629
Vanilloid receptor 1 (TRPV1), a nonspecific cation channel expressed primarily in small sensory neurons, mediates inflammatory thermal pain sensation. The function and expression of TRPV1 are enhanced during inflammation and certain neuropathies, leading to sustained hyperalgesia. Activation of TRPV1 in the spinal cord and periphery promotes release of adenosine, which produces analgesia by activating A1 and A2A adenosine receptor (AR) on central and peripheral neurons. This study provides evidence of a direct interaction of AR analogs with TRPV1. Adenosine analogs inhibit TRPV1-mediated Ca2+ entry in human embryonic kidney (HEK293) cells stably expressing TRPV1 (HEK/TRPV1) and DRG neurons. This inhibition was independent of A2AAR activation. Specific binding of [3H]resiniferatoxin (RTX) in plasma membrane preparations was inhibited by CGS21680
an A2AAR agonist. Similar degrees of inhibition were observed with both agonists and antagonists of ARs. Adenosine analogs inhibited [3H]RTX binding to affinity-purified TRPV1, indicative of a direct interaction of these ligands with the receptor. Furthermore, specific capsaicin-sensitive binding of [3H]CGS21680 was observed in Xenopus oocyte membranes expressing TRPV1. Capsaicin-induced inward currents in DRG neurons were inhibited by adenosine and agonist and antagonist of A2AAR at nanomolar concentrations. Increasing the concentrations of capsaicin reversed the inhibitory response to capsaicin, suggesting a competitive inhibition at TRPV1. Finally, exposure of HEK/TRPV1 cells to capsaicin induced an 2.4-fold increase in proapoptotic cells that was abolished by adenosine analogs. Together, these data suggest that adenosine could serve as an endogenous inhibitor of TRPV1 activity by directly interacting with the receptor protein.
Key words: TRPV1; adenosine; adenosine receptor; capsaicin; dorsal root ganglion; apoptosis
Received Oct 22, 2003; revised February 23, 2004; accepted February 24, 2004.
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