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A Painful Role for Ankyrin Repeats

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Science  06 Jul 2007:
Vol. 317, Issue 5834, pp. 19
DOI: 10.1126/science.317.5834.19c

Transient receptor potential (TRP) channels are nonselective cation channels that sense heat and noxious chemicals, and hence are important in nociception. One family member, TRPV1, responds to capsaicin, the “hot” ingredient of chilli peppers. TRP channel activity is reduced by either desensitization (after prolonged exposure to a single stimulus) or tachyphylaxis (after sequential exposures to the same stimulus). Increased intracellular Ca2+ desensitizes TRPV1 currents, and this desensitization may be mediated by the calcium-binding protein calmodulin (CaM). Lishko et al. solved the crystal structure of the ankyrin repeat domain (ARD) found in the N terminus of TRPV1. They discovered that adenosine 5′-triphosphate (ATP), present in the crystallization solution, bound to the ARD. ATP-agarose formed a complex with purified TRPV1-ARD, which was inhibitable by free ATP. Patch-clamp assays of TRPV1-expressing cells showed that ATP sensitized TRPV1 and reduced tachyphylaxis after repeated exposure to capsaicin. Surprisingly, mutation of residues in the ATP-binding site generated mutant TRPV1 channels that had reduced tachyphylaxis, even in the absence of ATP. This suggested that another factor that promotes tachyphylaxis must bind to the same site on TRPV1, and that mutations of this site would result in a net decrease in tachyphylaxis. Exclusion chromatography analysis showed that CaM formed a complex with TRPV1-ARD that was Ca2+-dependent and inhibitable by ATP. Together, these data reveal how the ARD of TRPV1 supports the sensitizing effect of ATP and the inhibitory effect of CaM. — JFF

Neuron 54, 905 (2007).

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