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- Title
Structure and function of IP<sub>3</sub> receptors.
- Authors
Taylor, Colin W.
- Abstract
Inositol 1,4,5-trisphosphate receptors (IP3R) are intracellular Ca2+ channels that are expressed in almost all animal cells. They mediate both the initial release of Ca2+ from intracellular stores evoked by the many receptors that stimulate IP3 formation and the regenerative propagation of intracellular Ca2+ signals. The latter depends upon both the regulation of IP3R by Ca2+ and the appropriate spacing of IP3R such that Ca2+ released by one IP3R can regulate the activities of its neighbours. This highlights a recurrent theme in intracellular signalling: the importance of spatially organised signalling pathways. I will illustrate, using patch-clamp recording, how IP3 dynamically regulates the assembly of IP3RS into small clusters wherein their behaviour is very different from lone IP3R. This IP3-regulated clustering re-tunes the IP3 and Ca2+ sensitivities of IP3R, facilitating the regenerative propagation of intracellular Ca2+ signals. A second universal theme is the integration of signals from different signalling pathways. Here too, IP3R illustrates some of the principles. The essential regulators of IP3R are IP3 and Ca2+, but many additional signals modulate their effects, thereby endowing IP3R with considerable computational ability. I will focus on one example of an interaction between two ubiquitous signalling pathways, cAMP and Ca2+, that serves also further to highlight the importance of spatial organization. I will present evidence that cAMP is delivered directly to IP3R from adenylyl cyclase (AC), within junctions that are formed specifically between type 6 AC and type 2 IP3R. These junctions function as robust on-off switches, in contrast to the responses of more typical cAMP effectors like PKA, which bind cAMP with greater affinity, and respond to local cAMP gradients extending over greater distances from AC. This defines two modes of cAMP signalling: binary (IP3R) where cAMP is delivered directly to a low-affinity target and diffusion is sufficient to turn of the signal, and analog (eg PKA) where a higher affinity cAMP target responds to a cAMP gradient, but local degradation is required to maintain local signalling events.
- Publication
Cell Membranes & Free Radical Research, 2008, Vol 1, Issue 1, p1
- ISSN
1308-416X
- Publication type
Article