The Role of Intracellular Calcium and Adenosine Triphosphate in the Modulation of the Canonical Transient Receptor Potential Channels – 4 (TRPC4)

Abstract

TRPC4 is a tetrameric, non-selective, calcium permeable cation channel that has been implicated in a variety of pathologies, including GI motility disorders. TRPC4 is activated by M1 or M2 muscarinic receptors that are also coupled to G-proteins (GPCRs). Stimulation of M1 receptors leads to activation of the Gq11 G-protein, the downstream effect of which is release of calcium from intracellular stores. Intracellular calcium activates a close relative of TRPC4, the TRPC5 channel. Activation of M2 receptors leads to activation of the Gi/o G-protein, inhibition of adenylyl cyclase and a decrease in synthesis of cyclic adenosine-monophosphate (cAMP) from adenosine triphosphate (ATP). The result is a preservation of sub-local intracellular ATP concentrations. Intracellular ATP inhibits TRPC5. However, unlike TRPC5, it is not known which components of the G-protein pathways directly interact with TRPC4 to activate the channel. Since TRPC5 and TRPC4 are most closely related out of all TRP channels, TRPC5 was used as a guide, and the effects of intracellular calcium (Gq11) and ATP (Gi/o) on TRPC4 were evaluated. Unlike TRPC5, intracellular calcium did not activate TRPC4; and unlike TRPC5, intracellular ATP potentiated TRPC4. This shows two very distinct differences between two channels that were previously thought to be quite similar. Additionally, gastrointestinal motility disorders are associated with TRPC4 channels. Muscarinic-induced currents and motility are impaired when TRPC4 is knocked out in rodent models. Identifying and understanding how TRPC4 channels are modulated by G-protein pathway components can provide novel insight and potential therapy targets for some gastrointestinal pathologies.