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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, and Vickram 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 A_2A 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 A_2AAR activation. Specific binding of [³H]resiniferatoxin (RTX) in plasma membrane preparations was inhibited by CGS21680 an A_2AAR 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 A_2AAR 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

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Received Oct 22, 2003; revised February 23, 2004; accepted February 24, 2004.

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