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Defining the stoichiometry of inositol 1,4,5-trisphosphate binding required to initiate Ca2+ release

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Science Signaling  05 Apr 2016:
Vol. 9, Issue 422, pp. ra35
DOI: 10.1126/scisignal.aad6281

Four says, “Open!”

Intracellular calcium regulates such specialized processes as muscle contraction, neurotransmitter release, and insulin secretion and such general cellular processes as gene expression, proliferation, and cell death. The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) plays key roles in increasing intracellular calcium by functioning as a channel that releases Ca2+ from the endoplasmic reticulum. The IP3R is a tetramer with each subunit having a binding site for IP3. Alzayady et al. determined how many subunits have to bind IP3 for the channel to open by engineering versions of the receptor expressed as a single protein with different numbers of IP3-binding sites. Analysis of these concatenated receptor proteins revealed that channel activity required IP3 bound to each of the four binding sites, which ensures that cells do not discharge calcium unless the signal to do so is strong enough. A similar approach could be used to define how heterozygous mutations in IP3R subunits produce disease.

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