Molecular determinants of ligand interaction with the capsaicin receptor

Abstract

Birds are indifferent to the pain‐producing effects of capsaicin. However, avian primary sensory neurons exhibit heat‐evoked membrane currents resembling those carried by mammalian capsaicin receptors. We aimed to identify an avian capsaicin receptor homolog, and to map structural determinants for vanilloid sensitivity. We cloned the avian capsaicin receptor ortholog, cVR1 (68% identity to rat VR1), from a chicken DRG library. cVR1 currents responded to noxious heat and acidity, but were insensitive to capsaicin. Structural domains essential for vanilloid interaction were mapped by chimeric analysis, ligand binding assays, mutagenesis and chemical labeling. Vanilloid sensitivity can be conferred to vanilloid‐insensitive capsaicin receptor homologs (cVR1, VRL1 and TRPV4) by a domain within the transmembrane moiety of rat VR1. Genetic and chemical modification studies suggest that capsaicin or the endogenous ligand, anandamide, bind to the receptor from the intracellular side of the plasma membrane and interact with residues near the third putative transmembrane region.