Non-conducting functions of voltage-gated ion channels

In addition to their well-understood role in determining the electrical activity of neurons, there exists evidence linking the expression of specific channels to cell proliferation. Such evidence has been obtained for several voltage-dependent K+ and Na+ channels and for several members of the non-selective TRP family of channels.The pore-forming α-subunit of ether-à-go-go (EAG) channels has been found to activate Ca2+/calmodulin-dependent protein kinase II (CaMKII). The conformation of this channel has also been found to be coupled to the mitogen-activated protein kinase (MAPK) signalling pathway through a mechanism that is independent of ion flux through the channel.Overexpression of the voltage-dependent Shal K+ channel in lobster neurons produces a compensatory increase in HCN channel activity. The increase in non-selective cation current opposes the increase in Shal K+ current, allowing the neurons to maintain their physiological pattern of bursting.The β-subunits of K+ channels have been found to have various intrinsic enzyme activities. These include protein kinase and aldo reductase functions, and transcription factor activity.The β-subunits of voltage-dependent Na+ channels have large extracellular domains that mediate cell–cell adhesion and repulsion, or promote neuriteoutgrowth through interactions with other cell adhesion molecules or through interactions with β-subunits on other cells.Neuronal voltage-dependent Ca2+ channels can be linked directly to the synaptic release machinery at presynaptic endings. The conformation of these channels might also directly modulate the exocytosis of synaptic vesicles.Transient activation of neuronal voltage-dependent Ca2+ channels activates the MAPK/ERK signalling pathway, resulting in activation of the transcription factor CREB. The activation of this pathway requires a local interaction between Ca2+ entering the channel and calmodulin, which is tightly bound to the C-terminus of the channel protein.Non-selective cation channels of the TRP family have a variety of cellular actions that could be a result of their ability to interact with cytoplasmic elements. The α-subunits of some TRPM subfamily channels have intrinsic protein kinase activity, and subunits of the TRPP subfamily can regulate cell proliferation and morphogenesis by mechanisms partially independent of ion conduction.