Ion Channel Regulation By Signal Transduction Pathways

Environmental Health Sciences

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Abstract

We have focused on three specific ion channels:[unreadable] [unreadable] -The CaV1.2 calcium channels which are encoded by the CaCNA1C gene and link depolarization to hormone secretion, muscle contraction, and neuronal gene expression. Many human diseases result from inherited mutations that disrupt the function of ion channel proteins. Now we have discovered two human disorders that arise from too much activity of one type of calcium channel. Although calcium triggers many essential cellular processes, prolonged increases in calcium inside the cell are toxic. Our studies of calcium channel regulation by calcium-dependent protein kinases and phosphatases have led to the discovery that the immunosuppressant cyclosporin, which inhibits the calcium-dependent protein phosphatase calcineurin, and Timothy syndrome, a multi-organ disorder of the heart and brain produced by mutation of the CaV1.2 channel, both increase channel phosphorylation by the calcium/calmodulin-dependent protein kinase CAMKII, which results in unregulated channel opening (Erxleben C et al. 2006).[unreadable] [unreadable] -The Kv11.1 (hERG) potassium channels, which are encoded by the KCNH2 gene and regulate action potential frequency in endocrine cells and neurons. We discovered previously that hormonal regulation of hERG channels in rat pituitary cells is mediated by Rho family GTPases, which are better known for their regulation of cytoskeleton. We showed that Rho mediates hERG inhibition by the hypothalamic neuropeptide, thyrotropin releasing hormone (TRH), which stimulates pituitary excitability and hormone release through Gq and G13 coupled GPCRs, while Rac mediates the opposing effect of thyroid hormone (Storey et al 2002). This was the first demonstration of a specific role for the cytoplasmic Ras-related Rho GTPases in hormonal regulation of ion channels. We have gone on to show that Rho GTPases regulate hERG activity through reversible protein phosphorylation of a specific site in the cytoplasmic C terminus of the channel protein. Rac stimulates the PP5 protein phosphatase (Gentile et al 2006) and Rho stimulates a protein kinase (Gentile & Martin, unpublished).[unreadable] [unreadable] -The BKca potassium channels, which are encoded by the KCNMA1 gene (slo) and regulate action potential duration in endocrine cells and nerve terminals. Genetic studies of ethanol action on locomotor coordination in invertebrate model organisms have identified BKca channels as a prominent target of ethanol action. Other studies have identified the Gs-cAMP-PKA signaling system as a target of ethanol action. Therefore, we have studied the mechanism of mammalian BKca regulation by ethanol in pituitary cells and recombinant systems. All our data are consistent with a role for the Ser/Thr targeted protein phosphatase, PP1 as essential for ethanol action (Ma et al, unpublished). We have confirmed this dependence of ethanol action on PP1 activity in rat hippocampal slices, in which ethanol inhitis LTP on CA1 pyramidal dendrites (Zhang et al, unpublished).