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E-Conference: Defining Calcium Entry Signals

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Agonist-mediated calcium entry - contiguous ER or ER resident proteins?

1 June 2004

Randen L Patterson

A role for the ER in the activation and modulation of receptor activated (G-protein coupled or tyrosine kinase coupled) calcium entry at the plasma membrane is questionable; however a role for resident proteins of the ER seems indisputable. In particular, the number of papers demonstrating a physical and functional interaction of the IP3-receptor with plasma membrane ion channels, in particular TRPC channels, is growing rapidly. A quick summary of this work details a direct physical interaction of the IP3-recpetor with TRPC channels, and that this interaction is capable of gating these channels in the presence of IP3 in response to plasma-membrane receptor stimulation. The undefined variable in this equation is whether these IP3-receptors are part of the contiguous ER, or are they in other membrane pools, perhaps even the plasma membrane.

A reasonable hypothesis, building from the model proposed in the 1995 review by Michael Berridge, is that IP3-recpetors coupling to calcium entry would be in a “release-dead” conformation, or alternatively on membranes/vesicles which do not contain high levels of calcium. This model is supported by the work of many, including us, showing that the N-terminus of the IP3-receptor is capable of gating calcium entry independent of its calcium release functions. Additionally, as calcium entry channels tend to be inhibited by calcium, release of calcium from IP3-receptors coupled to this process would likely be counter-productive.

These same statements would hold true for a role of the ryanodine receptor coupling to calcium entry channels, although the data supporting this idea is tenuous at best.

A role for SERCA, another major calcium handling component of the ER, is also under-defined in receptor-activated calcium entry. A few manuscripts have demonstrated changes increases in SERCA activity following agonist stimulation, but a molecular mechanism has yet to be elucidated. The only hypothesis that can be drawn currently is that SERCA activity is used in conjunction with the plasma-membrane calcium ATPase, sodium/calcium exchanger, mitochondria, and other calcium storage units to tightly regulate intracellular calcium levels during stimulation, with the orchestration of these many components allowing for multiple cellular outputs (growth, gene transcription, hormone secretion etc.).

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