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E-Conference: Defining Calcium Entry Signals

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TRP channels as non-selective cation channels

18 June 2004

Kenneth L. Byron

As the focus of this forum is defining Ca2+ entry signals, we have perhaps limited our view of the roles of Ca2+-permeable ion channels.

For example, consider the statement "TRPC6 is highly expressed in vascular smooth muscle cells, it represents a likely molecular candidate for the vasoconstrictor-activated Ca2+-permeable cation channel." Although I agree with that statement, I wonder about the emphasis on Ca2+ permeability of TRPC6.

The electrophysiological evidence from either exogenously expressed TRPC6 channels or endogenously expressed channels that have been attributed to TRPC6 in vascular smooth muscle cells indicates that these are non-selective cation channels. I am not aware of any evidence that, under physiological agonist concentrations and ionic conditions, the entry of Ca2+ via these channels directly elicits a physiological response in vascular smooth muscle cells.

I think we ought to keep in mind that in excitable cells such as vascular smooth muscle, the primary role of activation of non-selective cation channels may be to depolarize the membrane and consequently activate voltage-sensitive Ca2+ channels. In fact Na+ entry may be more important than Ca2+ entry under physiological conditions.

Some members of the TRPC family, e.g. TRPC4 and TRPC5, at least as homotetramers, may function as monovalent cation channels, but may nonetheless contribute to Ca2+ entry via membrane potential effects in excitable cells.

Even in non- excitable cells Na+ entry via non-selective Ca2+-permeable channels may be important for physiological responses. Focusing specifically on Ca2+ entry, a consequence of Na+ entry may be reverse mode Na+/Ca2+ exchange, which may have important localized effects at regions of close apposition between plasma membrane and ER and may even account for some of the sustained Ca2+ signals measured using fluorescent Ca2+ indicators.

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