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Cellular |
1 Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, OH 44109, USA
2 Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
TRPC6 is thought to be a Ca2+-permeable cation channel activated following stimulation of G-protein-coupled membrane receptors linked to phospholipase C (PLC). TRPC6 current is also activated by exogenous application of 1-oleoyl-acetyl-sn-glycerol (OAG) or by inhibiting 1,2-diacylglycerol (DAG) lipase activity using RHC80267. In the present study, both OAG and RHC80267 increased whole-cell TRPC6 current in cells from a human embryonic kidney cell line (HEK 293) stably expressing TRPC6, but neither compound increased cytosolic free Ca2+ concentration ([Ca2+]i) when the cells were bathed in high-K+ buffer to hold the membrane potential near 0 mV. These results suggested that TRPC6 channels have limited Ca2+ permeability relative to monovalent cation permeability and/or that Ca2+ influx via TRPC6 is greatly attenuated by depolarization. To evaluate Ca2+ permeability, TRPC6 currents were examined in extracellular buffer in which Ca2+ was varied from 0.02 to 20 mM. The results were consistent with a pore-permeation model in which Ca2+ acts primarily as a blocking ion and contributes only a small percentage (
4%) to whole-cell currents in the presence of extracellular Na+. Measurement of single-cell fura-2 fluorescence during perforated-patch recording of TRPC6 currents showed that OAG increased [Ca2+]i 50–100 nM when the membrane potential was clamped at between –50 and –80 mV, but had little or no effect if the membrane potential was left uncontrolled. These results suggest that in cells exhibiting a high input resistance, the primary effect of activating TRPC6 will be membrane depolarization. However, in cells able to maintain a hyperpolarized potential (e.g. cells with a large inwardly rectifying or Ca2+-activated K+ current), activation of TRPC6 will lead to a sustained increase in [Ca2+]i. Thus, the contribution of TRPC6 current to both the kinetics and magnitude of the Ca2+ response will be cell specific and dependent upon the complement of other channel types.
(Received 6 December 2005;
accepted after revision 25 January 2006;
first published online 26 January 2006)
Corresponding author W. P. Schilling: Rammelkamp Center for Education and Research, Room R-322, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998, USA. Email: wschilling{at}metrohealth.org
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