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. 2016 Apr 5;9(422):pe1.
doi: 10.1126/scisignal.aaf6029.

IP3 receptors: Take four IP3 to open

Colin W Taylor  1 , Vera Konieczny  2
Affiliations

IP3 receptors: Take four IP3 to open

Colin W Taylor et al. Sci Signal. .

Abstract

Inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors are the channels responsible for Ca(2+)release from the endoplasmic and sarcoplasmic reticulum. Research inScience Signalingby Alzayadyet al show that all four IP3-binding sites within the tetrameric IP3R must bind IP3before the channel can open, which has important consequences for the distribution of both IP3and IP3R activity within cells.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1. Structure of the IP3R
(A) The essential 4- and 5-phosphate groups of IP3 bind to opposite sides (β- and α-domains) of the clam-like IP3-binding core (IBC) causing the clam to close and re-position the suppressor domain (SD), which moves with the α-domain of the IBC (Protein Data Bank, PDB, 3U4J) (5). Locations of key domains within the primary sequence are shown below. (B) View from the cytosol showing the four N-terminal regions (SD and IBC) and the C-terminal domains (CTD) from each subunit (the central splayed α-helices). The coloured subunits (orange and green) show how the CTD from one subunit contacts the N-terminal region (the β-IBC) of another. The N- (blue) and C-termini (red) of each subunit, through which Alzayady et al. linked subunits to form concatamers (16), are highlighted; the termini of one subunit are enclosed in the yellow box. Within each IBC, the position where IP3 would bind is shown by a yellow circle (PDB, 3JAV) (11). (C) View across the ER membrane, with 2 subunits highlighted in shades of orange and green. The transmembrane region with its 24 α-helices, six from each subunit, are shown (PDB, 3JAV) (11). (D) One of the likely inter-subunit interactions through which IP3R binding to the IBC is communicated to the pore. The β-domain of the IBC of one subunit contacts the C-terminal domain (CTD) of another. The CTD extends as an almost unbroken α-helix through the centre of the protein to helix S6, which lines the pore. For the pore to open and allow Ca2+ to pass, S6 must move to disrupt the hydrophobic constriction that occludes the closed pore (red arrow).
Fig. 2
Fig. 2. IP3Rs bind and buffer IP3
(A) Within a typical cell, the concentration of IP3-binding sites and their affinity (KD) for IP3 are similar (~100nM). An inescapable consequence is that within the range of IP3 concentrations that achieve graded occupancy of the binding sites, a substantial fraction of the IP3 is bound, thereby depleting the cytosol of free IP3 (18). (B) Buffering of cytosolic IP3 by IP3R shifts the relationship between IP3 concentration and IP3 binding to higher concentrations of IP3: a total concentration that exceeds the KD is now required to occupy 50% of the binding sites. Because 4 sites must be occupied to activate an IP3R, the IP3 concentrations needed to activate 50% of IP3Rs are much higher than those needed to occupy 50% of the binding sites. In this simple scheme, a concentration of IP3 that occupied 50% of all binding sites, would allow only 6% of all IP3Rs, about 450 IP3Rs in a typical cell, to bind the 4 IP3 needed for activity. (C) IP3 produced by PLC is captured by IP3Rs as it diffuses into the cytosol creating a radial concentration gradient. Within the gradient, IP3Rs very close to PLC may acquire the 4 IP3 molecules needed for activity (green), but beyond that there is an extensive penumbra of IP3Rs that bind IP3 to fewer of their subunits.
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