E-Conference: Defining Calcium Entry Signals
Comment on processes that mediate activation of calcium entry channels
8 June 2004
Kenneth L. Byron
I’d like to respond briefly to comments made by Don and by Jim Putney.
Don writes: “Whereas the conformational coupling model has been an attractive scheme and has derived some support from the possible role of InsP3Rs, we consider that the analogy of this model with the functioning of the triad junction in skeletal muscle is somewhat flawed… In reality, however, the triad junction in muscle serves as an exceedingly rapid means for sensing and transducing the electrical signal in the plasma membrane into a Ca2+ release signal from the SR. In contrast, the store-operated signal takes many seconds or even minutes to develop and is, hence, unlikely to require a similar rapid and direct coupling process.”
I’m not sure what “store-operated signal” Don refers to or in fact what we ought to monitor to determine the kinetics of store-operated signaling. The Ca2+ overshoot measured in fura-2 fluorescence studies may reflect a non-physiological spillover of Ca2+ that either cannot be taken up into the stores because we’ve inhibited the SERCA pumps or that exceeds normal physiological concentrations because we’ve used supraphysiological concentrations of agonists. Under physiological conditions (low agonist concentrations) perhaps, as postulated by Jim, even a small release of Ca2+ is sufficient to rapidly trigger a small (undetectable by conventional methods) Ca2+ entry to refill the ER Ca2+ stores.
I think it’s possible that in oscillatory Ca2+ responses the coupling between stores and plasma membrane may be very rapid, perhaps approaching the muscle triadic junction model. There may be some built-in difference in kinetics that is unrelated to conformational coupling per se, which relates to the fact that the signal goes from inside out rather than outside in. There may be a temporal lag for example if the concentration of Ca2+ inside the stores must be reduced to some threshold level before the store-operated signal is activated. Electrophysiological measurements of store-operated currents are generally conducted under even more non-physiological conditions, so the kinetics of their activation may not reflect the normal coupling between store depletion and Ca2+ entry.
With regard to the statement “We are realizing that TRPC channels (as well as other TRP channel members) are channels receiving multiple inputs. We think of them as "integrators" of a number of signals, their opening reflecting the summation of multiple distinct signals.”, I don’t particularly like the notion that individual TRPC channels integrate signals from so many different areas. I don’t think there is sufficient experimental evidence to support either case, but I would favor the notion that distinct channel assemblies can respond to localized receptor activation, while others are positioned (and probably comprised of different auxiliary proteins or have different TRP channel homologue stoichiometry) to respond to store depletion or other signals.
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