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Review
. 2010 Dec;2(12):a004010.
doi: 10.1101/cshperspect.a004010. Epub 2010 Oct 27.

IP(3) receptors: toward understanding their activation

Colin W Taylor  1 , Stephen C Tovey
Affiliations
Review

IP(3) receptors: toward understanding their activation

Colin W Taylor et al. Cold Spring Harb Perspect Biol. 2010 Dec.

Abstract

Inositol 1,4,5-trisphosphate receptors (IP(3)R) and their relatives, ryanodine receptors, are the channels that most often mediate Ca(2+) release from intracellular stores. Their regulation by Ca(2+) allows them also to propagate cytosolic Ca(2+) signals regeneratively. This brief review addresses the structural basis of IP(3)R activation by IP(3) and Ca(2+). IP(3) initiates IP(3)R activation by promoting Ca(2+) binding to a stimulatory Ca(2+)-binding site, the identity of which is unresolved. We suggest that interactions of critical phosphate groups in IP(3) with opposite sides of the clam-like IP(3)-binding core cause it to close and propagate a conformational change toward the pore via the adjacent N-terminal suppressor domain. The pore, assembled from the last pair of transmembrane domains and the intervening pore loop from each of the four IP(3)R subunits, forms a structure in which a luminal selectivity filter and a gate at the cytosolic end of the pore control cation fluxes through the IP(3)R.

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Figures

Figure 1.
Figure 1.
Regulation of IP3R by cytosolic and luminal Ca2+. (A) Binding of IP3 (black circle) to the IP3R determines whether a stimulatory (green) or inhibitory (red) Ca2+-binding site is available (Adkins and Taylor 1999). IP3 binding causes the stimulatory site to become accessible and the inhibitory site to be concealed; binding of Ca2+ (blue circle) to the former then triggers opening of the channel. (B) Luminal Ca2+ is proposed to tune the sensitivity of the IP3R to cytosolic IP3 and Ca2+ such that full stores (i) are most sensitive to IP3. As the IP3R opens (ii) and the stores lose Ca2+, they are proposed to lose sensitivity to IP3 until eventually the IP3R closes, despite the continued presence of the cytosolic stimuli, trapping Ca2+ within the ER (iii). Conversely, stores regain their sensitivity to IP3 as the stores refill, perhaps thereby determining the interval between Ca2+ spikes in stimulated cells (Berridge 2007).
Figure 2.
Figure 2.
Major structural domains of IP3R. (A) The three key regions defined by the primary sequence of a single IP3R subunit are highlighted: the N-terminal with its SD and IBC, the C-terminal region with its six TMD and pore, and the large central region. Atomic structures of the SD (Bosanac et al. 2005) and IBC with IP3 bound (Bosanac et al. 2002) are also shown. (B) Two views of the IP3R derived from single particle analysis (da Fonseca et al. 2003) (top, from the cytosol; bottom, across the ER membrane with the ER lumen at the top). (C) A possible structure of the IP3R pore, with a luminal selectivity filter and a constriction formed by the tepee-like structure of TMD6. Only two of the four IP3R subunits are shown.
Figure 3.
Figure 3.
Initiation of IP3R activation by IP3. (A) The structure of IP3, with its critical vicinal 4,5-bisphosphate and 6-hydroxyl groups, is shown alongside the structure of the IBC with IP3 bound. The latter shows the 4- and 5-phosphates contacting the β- and α-domains, respectively (Bosanac et al. 2002), and thereby pulling the clam into a more closed state. (B) Structure of the SD (Bosanac et al. 2005) showing possible sites of interaction with the IBC and downstream domains through which it signals to the pore. See text for further details.
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