Potassium channels at the beginnings of cell proliferation

In physiology it is common to think of the vascular smooth muscle cell in its contractile phenotype, orientated radially and contracting to regulate blood flow. However, in response to growth factors and other environmental signals these cells may lose their contractile traits in favour of a phenotype characterized by shape change, migration and proliferation. Such plasticity is important in physiology for new blood vessel development, but also contributes significantly to vascular diseases including atherosclerosis (Owens et al. 2004). The molecular machinery governing smooth muscle cell behaviour is of course complex and multifactorial. One important theme is ion channels, as is apparent in reviews within this issue of The Journal of Physiology. Ion channels are able to regulate different patterns of rhythmicity in smooth muscle tissues and control calcium influx, which is important for contraction but also profoundly influences many other cellular mechanisms. Probably the first directly observed ion channel of vascular smooth muscle cells – over two decades ago – was the large conductance calcium-activated potassium channel (commonly known as BKCa or maxiK; or in IUPHAR nomenclature KCa1.1). This channel is activated by elevated intracellular calcium and depolarization, and is reviewed in this issue by Lu et al. (2006). In contractile smooth muscle cells it provides hyperpolarizing counter balance against depolarization, limiting calcium-influx through L-type voltage gated calcium channels. When the cells switch to proliferative phenotype, BKCa is, however, down-regulated, along with the L-type calcium channel (Neylon et al. 1999). This does not mean that calcium and ion channels become unimportant but, for reasons not well understood, the proliferating cells use other ion channels. One of these is the intermediate conductance calcium-activated potassium channel (commonly known as IKCa, or in IUPHAR nomenclature KCa3.1). Unlike BKCa, IKCa does not depend on depolarization to facilitate its opening and thus can open at more hyperpolarized membrane potentials. It is suggested this is useful for cells having lost L-type calcium channels, i.e. that hyperpolarization driven by IKCa serves to enhance the electrochemical gradient for calcium entry through voltage-independent calcium channels. Consistent with this hypothesis, blockade of IKCa suppresses vascular smooth muscle cell proliferation and neointimal hyperplasia (Neylon et al. 1999; Cheong et al. 2005). Intriguingly, lymphocyte activation (Chandy et al. 2004) and proliferation in other cell types involves a similar mechanism, suggesting potassium channel activation and the consequent hyperpolarization of the membrane potential is a conserved and key mechanism enabling cell proliferation. In this issue of The Journal of Physiology, Ivanov et al. (2006) address an important question: how might a growth factor – in this case epidermal growth factor (EGF) – initiate the process of phenotypic modulation when the contractile smooth muscle cells express BKCa and not IKCa? In an elegant series of experiments including electrophysiology and injection into the cisterna magna they make progress towards answering the question, critically showing that EGF and related EGF-receptor ligands hyperpolarize smooth muscle cells of the basilar artery by activating BKCa, and that iberiotoxin – a highly specific blocker of BKCa– prevents EGF-evoked induction of a cell proliferation marker in vivo. Unanswered is how this BKCa-mediated hyperpolarization might lead to cell proliferation. With reference to a study of transient receptor potential channels in neuronal growth cones Ivanov et al. (2006) suggest EGF might concomitantly induce voltage-independent calcium entry channels. By implication, L-type calcium channels might also be expected to be down-regulated. Furthermore, there is the matter of EGF evoking hyperpolarization in the context of its observed role as a potent vasonconstrictor. These will be important matters to address in future studies. At this stage, Ivanov et al. provide good supporting data for the central importance of potassium channels in the early phases of cell proliferation, revealing that existing BKCa channels of contractile vascular smooth muscle cells can serve this function prior to the transition to IKCa.