Receptor-mediated regulation of the TRPM7 channel through its endogenous protein kinase domain

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FONTE

National Academy of Sciences

RESUMO

TRPM7 is a ubiquitously expressed and constitutively active divalent cation-selective ion channel, whose basal activity is regulated by intracellular levels of Mg2+ and Mg·ATP. We have investigated receptor-mediated mechanisms that may actively regulate TRPM7 activity. We here report that TRPM7 currents are suppressed by intracellular GTPγS, suggesting the involvement of heterotrimeric G proteins. TRPM7 currents are also inhibited by stimulating endogenous muscarinic receptors, which is mediated by Gi because the inhibitory effect is blunted by pertussis toxin. Conversely, stimulation of endogenous Gs-coupled β-adrenergic receptors potentiates TRPM7 currents, whereas Gq-coupled thrombin receptors have little effect. Consistent with the involvement of Gs/Gi in controlling adenylyl cyclase activity, elevations of intracellular cAMP levels enhance TRPM7 activity and prevent receptor-mediated modulation of TRPM7 activity by muscarinic and adrenergic agonists. This cAMP-dependent effect requires the functional integrity of both protein kinase A (PKA) and the endogenous kinase domain of TRPM7 because cAMP-mediated effects are abolished when treating cells with the PKA inhibitors H89 or KT5720 as well as in cells expressing phosphotransferase-deficient TRPM7 constructs. These mutant channels are also much less susceptible to GTPγS-mediated inhibition, suggesting that the main regulatory effect occurs through Gi- and Gs-mediated changes in cAMP. Taken together, our results demonstrate that TRPM7 activity is up- and down-regulated through its endogenous kinase in a cAMP- and PKA-dependent manner.

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