Phospholipase C not protein kinase C is required for the activation of TRPC5 channels by cholecystokinin.

Laurel A Grisanti, Lalitha Kurada, Nicholas I Cilz, James E Porter, Saobo Lei

European journal of pharmacology 2012 Aug 15

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Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain where it interacts with two G protein-coupled receptors (CCK1 and CCK2). Both types of CCK receptors are coupled to G(q/11) proteins resulting in increased function of phospholipase C (PLC) pathway. Whereas CCK has been suggested to increase neuronal excitability in the brain via activation of cationic channels, the types of cationic channels have not yet been identified. Here, we co-expressed CCK2 receptors and TRPC5 channels in human embryonic kidney (HEK) 293 cells and studied the effects of CCK on TRPC5 channels using patch-clamp techniques. Our results demonstrate that activation of CCK2 receptors robustly potentiates the function of TRPC5 channels. CCK-induced activation of TRPC5 channels requires the functions of G-proteins and PLC and depends on extracellular Ca(2+). The activation of TRPC5 channels mediated by CCK2 receptors is independent of IP(3) receptors and protein kinase C. CCK-induced opening of TRPC5 channels is not store-operated because application of thapsigargin to deplete intracellular Ca(2+) stores failed to alter CCK-induced TRPC5 channel currents significantly. Bath application of CCK also significantly increased the open probability of TRPC5 single channel currents in cell-attached patches. Because CCK exerts extensive effects in the brain, our results may provide a novel mechanism to explain its roles in modulating neuronal excitability. Copyright © 2012 Elsevier B.V. All rights reserved.

Citation

Laurel A Grisanti, Lalitha Kurada, Nicholas I Cilz, James E Porter, Saobo Lei. Phospholipase C not protein kinase C is required for the activation of TRPC5 channels by cholecystokinin. European journal of pharmacology. 2012 Aug 15;689(1-3):17-24