Kv1.3: the perfect opening of the platelet voltage gate.

Potassium channels are a vast family of transmembrane molecules with diverse functions in many cell types. They are subdivided according to mechanistic and structural criteria; the largest subclass comprising the voltage-gated K+-selective (Kv) channels. Kv channels have important signalling roles in both excitable and non-excitable cells and the efflux of positive charge that they elicit is linked with the function of other voltage-dependent ion channels. Thus, these channels can modify membrane potential and the flux of Na+ and Ca2+ ions, explaining their diverse roles. Kv channels have been implicated in cell secretion, volume regulation, integrin activation, apoptosis and proliferation and are putative drug targets for diseases including cancer, as well as neurological and metabolic syndromes (Wulff et al. 2009). The presence of Kv channels in blood cells, including platelets, implies roles in the differentiation, proliferation and function of these cell types, and the ability of platelet agonists to differentially modify their behaviour suggests acute functional roles that may prove important in haemostasis and in the development and progression of platelet-driven thrombotic events (Kapural & Fein, 1997). Platelets are well known as key drivers of arterial thrombotic events, such as myocardial infarction, and are cornerstones of pharmacological intervention in such conditions: aspirin selectively targets platelet cycloxygenase and clopidogrel prevents platelet activation by ADP. These therapies are, unfortunately, suboptimal since they are associated with bleeding risk and are ineffective in significant groups of patients. There is a clear need, therefore, for novel targets in the treatment of platelet-driven diseases. Could Kv channels, with their important signalling roles, provide a novel antithrombotic target in the platelet? There is a problem. There are a wide range of Kv channels: some 50 or more subtypes have been identified. Each channel subtype has been cloned, their structure and pharmacology have been well defined (Swartz, 2004) and knock-out lines created (Wulff et al. 2009). What has become apparent is that Kv channels have diverse and wide-ranging roles: some knock-out lines are rapidly fatal post-natal, others have much milder, and wildly varying, phenotypes. The lack of clarity concerning the identity of the Kv subtype(s) present in the platelets questions their viability as therapeutic targets, since the side-effects associated with targeted inhibition of these channels could, potentially, prohibit any clinical application. In a recent issue of The Journal of Physiology, McCloskey and colleagues (2010) set out to establish the molecular identity of the Kv subgroup present in platelets. Through quantitative PCR, the authors showed that only the Kv1.3 subunit was expressed at detectable levels. Kv1.3 has previously been detected in T and B cells, macrophages, the central nervous system and testes. Kv1.3 knock-out mice have increased insulin sensitivity (Xu et al. 2004) and low body weight (Xu et al. 2003) but are viable. McCloskey et al. used these mice to confirm that the effects of a pharmacological Kv1.3 antagonist were mediated selectively through this potassium channel subtype. Thus, the authors uncover the identity of the Kv subgroup present in platelets and demonstrate a functional role in the regulation of receptor-evoked [Ca2+]i increases, membrane potential and circulating platelet numbers. The identification of this particular channel, and the lack of evidence of a functional contribution from other subtypes, suggests that targeting of Kv1.3 is likely to profoundly affect platelet function and, potentially, thrombotic events. The importance of this work is highlighted by the authors through the demonstration of a regulatory role of Kv1.3 upon Ca2+ mediated signalling events but a lack of effect on megakaryoctye differentiation, permitting targeting of key second messenger systems in platelet-dependent thrombosis but normal platelet development. Kv1.3 was originally identified in human T cells (DeCoursey et al. 1984) and can suppress immune responses in vivo (Koo et al. 1997). Kv1.3 antagonists have also been effective in animal models of obesity and diabetes (Xu et al. 2003), both risk factors in the development of platelet-driven arterial thrombosis. The identification of Kv1.3 as a potential anti-platelet target raises the exciting possibility of a therapeutic target that abates the underlying causes of atherothrombosis, as well as the acute platelet-driven thrombotic event. In their paper, McCloskey et al. set the stage for further investigations of the role of Kv1.3 in regulating platelet functionality and as a therapeutic target in platelet-driven cardiovascular events.