Novel TRPM3 Agonist - Single Compound Opens Multiple Ion Permeation Pathways

Abstract

TRPM3 is a calcium-permeable nonselective cation channel in the melastatin (TRPM) subfamily of TRP channels. It represents a typical example of a polymodally gated TRP channel, in that it can be activated by chemical ligands such as nifedipine and the neurosteroid pregnenolone sulphate (PS), as well as by physical stimuli such as heat and membrane depolarization. Recently, we have found evidence for an alternative ion permeation pathway distinct from the central pore, which can be gated by combined application of PS and exogenous chemicals such as clotrimazole. This alternative ion permeation pathway is preserved following desensitization, blockade, mutagenesis and chemical modification of the central pore, and enables massive Na+ influx at negative voltages. By screening a compound library, we identified CIM021600 as potent agonist of TRPM3. The compound exhibited a marked specificity for TRPM3 and induced [Ca2+]I signals in somatosensory neurons. Intriguingly, single application of CIM021600 was able to activate both the central pore ion permeation pathway and the alternative ion permeation pathway. Since physiological functions of TRPM3 and the alternative ion permeation pathway of TRPM3 are still poorly defined, the identification of a potent and selective activator is expected to contribute to clarifying the role of TRPM3 in vivo.