Modulation of calcium signalling pathways

McCarron, J. and Chalmers, S. and Olson, M. (2011) Modulation of calcium signalling pathways. Journal of Vascular Research, 48 (Suppl.). p. 42. IS24. ISSN 1018-1172 (

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Ca2+ ions act as second messengers to transduce extracellular stimuli (e.g. those from hormones, neurotransmitters and growth factors) into a variety of intracellular activities which include cell division, contraction and cell death. Ca2+ is able to control and coordinate so many cellular functions because extracellular stimuli each evoke complex, spatially- and temporally-organized changes in cytoplasmic Ca2+ concentration ([Ca2+]c). Of particular significance, is the ability of cells to localize cytoplasmic Ca2+ signals to certain regions of the cell. It is this localization which enables the control of specific cellular activities to proceed from distinct regions. In these regions (microdomains) the Ca2+ concentration may significantly exceed the bulk average [Ca2+]c value. For example, depolarization of the plasma membrane activates a voltage-dependent Ca2+ current to evoke a rise in [Ca2+] in the subplasma membrane space and bulk cytoplasm. The rise in the bulk cytoplasm ([Ca2+]c) is approximately uniform throughout the cell - a feature that would usefully promote even contraction of the muscle cell. However, simultaneously, the Ca2+ rise in subplasma membrane space ([Ca2+]PM) has a wide range of amplitudes and time courses. The [Ca2+]PM variations reflect an uneven distribution of active Ca2+ channels (clusters) across the sarcolemma and enables local activation of specific effectors. In contrast to depolarisation-evoked Ca2+ rises, Ca2+ release from the internal store is not uniform throughout the bulk cytoplasm but begins at one site and progresses from there as a travelling spatial gradient of Ca2+ (a Ca2+ wave). Ca2+ waves are modulated in small regions of the cell by the local control of IP3R and RyR. Local activity of mitochondria specifically regulates the activity of IP3R to promote or inhibit wave progression. IP3R or RyR may also be controlled by endogenous proteins associated with the receptors, such as the 12 kDa FK506 binding protein (FKBP12), which may locally regulate release directly or indirectly via inhibition of the phosphatase calcineurin or via the kinase mammalian target of rapamycin (mTOR). Together, these processes and controls contribute to the generation of the complex Ca2+ signalling patterns that are required to transduce extracellular stimuli to physiological responses.


McCarron, J. ORCID logoORCID:, Chalmers, S. ORCID logoORCID: and Olson, M.;