Calcium Ion Channels

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In the communication of information throughout the body, voltage-gated ion channels are of special importance in maintaining a fast and accurate transmission of data.  The proper function thereof is essential to any sort of complex behavior, be it running, talking, learning, or even breathing.  In particular, the activity voltage-gated Ca2+ channels (VGCCs) directly affects both membrane potentials and neurotransmitter release, leading to the general interest surrounding its mechanisms of regulation.  It has been thus far well established that phosphatidylinositol 4,5-bisphosphate (PIP2) acts on VCGGs to produce two different behaviors: increased channel availability and decreased activation kinetics.

The hypothesized model for this kind of PIP2 activity suggests that two sites of action exist; at the “S” site, PIP2 increases current by promoting channel availability, while at the “R” site, PIP2 increases reluctant gating.  Based on studies done where VGCCs with PIP2 were exposed to antibodies against PIP2 or protein kinase A (PKA), the previous models suggests that the removal of PIP2 by cleavage by a lipase or other hydrolase is sufficient for decreasing current in VGCCs.

Increasingly though, research has shown that the activity of arachidonic acid (AA), a fatty acid available for liberation by lipase cleavage of PIP2, directly opposes that of PIP2 and argues that removal of active PIP2 alone is not sufficient, but is rather coupled with the activity of fatty acids such as AA.  Specifically, AA is a polyunsaturated fatty acid 20 carbons in length with a higher density of double bonds near the carboxy terminus.  Studies have examined its exogenous effects when applied to T-, L-, and N-type VGCCs and determined that, while all three varieties of channel respond differently, the unifying theme is that AA decreases channel availability by stabilizing closed conformations apparently through binding to the inner portion of cellular membrances while increasing channel sensitivity and promoting willing gating when binding to the outside of cellular surfaces.  Though these are not the only activities of AA and similar fatty acids, they are the best-defined at this juncture.

While not completely explained by current research, the new model of VGCC regulation requiring both PIP2 and AA for adequate reduction of VGCC activity explains a number of phenomena that fall short under the only-PIP2 model.  For example, Phospholipase A2 (PLA2), phospolipase C (PLC), and diacylglycerol lipase (DAG) have all been associated with decreased VGCC activity, but none have universally been able to do so with all types of VGCCs.

The data suggests that unified action of these three lipases to cleave PIP2 into its component parts with the pair of resulting fatty acids acting directly on the channel in question, whether through direct binding or otherwise, to inhibit overall activity.  As more research is done attempting to elucidate the exact mechanisms and specifics of this pathway, the model will likely evolve and become more concrete in the relationship between these portions of the signalling pathways.  Ultimately, the PIP2-AA model provides a system through which VGCC activity can be tightly controlled by modulation of multiple lipases as well as PIP2 or AA itself.

Additionally, it does not strictly contradict the idea or support of PIP2’s loss as sufficient for channel inhibition; rather, it takes the mechanism a step further to argue that a cascade of regulatory actions occurs as part of PIP2 cleavage and that these additionally modulate the VGCCs in question.  This model will be put to the test as studies in lipid regulation of VGCCs become more precise in their examination of the available pathways, but there is strong evidence to support the belief that joint protein-lipid mechanisms can best explain modulation of ion channels.

― Doug Hidlay

original paper: Roberts-Crowley ML et al. Regulation of voltage-gated Ca2+ channels by lipids. Cell Calcium. 45: 589–601 (2009).

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