Opening of an alternative ion permeation pathway in a nociceptor TRP channel

Besides the canonical pore that allows passage of cations into the cell, the TRPM3 channel has an alternative 'omega' permeation pathway formed by the S1–S4 region of the protein. This peripheral pore is inwardly rectifying, whereas the canonical central axis pore is outwardly rectifying. Sensory neurons detect chemical stimuli through projections in the skin and mucosa, where several transient receptor potential (TRP) channels act as primary chemosensors. TRP channels are tetramers, and it is generally accepted that binding of ligands causes the opening of a single central cation-conducting pore. Contrary to this view, we here provide evidence for a second permeation pathway in the TRP channel TRPM3, which can be gated by combined application of endogenous neurosteroids and exogenous chemicals such as clotrimazole or several structurally related drugs. This alternative pathway is preserved following desensitization, blockade, mutagenesis and chemical modification of the central pore and enables massive Na+ influx at negative voltages. Opening of this alternative pathway can enhance excitation of sensory neurons and thereby exacerbate TRPM3-dependent pain. Our findings indicate that a single sensory TRP channel can encompass two distinct ionotropic chemoreceptors, which may have important ramifications for TRP channel function and pharmacology.