Voltage-gated potassium (Kv) channels regulate cell membrane potential and control a variety of cellular processes. In last months “Target of the Month” we highlighted Kv1.5 and the ability of Kv1.3 gene transfer to limit the development of pulmonary hypertension. Likewise in this edition of TherapeuticAdvances “Focus on Immunology & Inflammatory Diseases” highlight field leading research from Merck & Co relating to the development of Kv1.3 channel inhibitors that limit T cell proliferation and activation and which may be useful in the treatment of autoimmune disease.

In addition to being involved in T cell function, examination of Kv1.3-deficient mice revealed a previously unrecognized role for Kv1.3 in body weight regulation. Indeed, Kv1.3(-/-) mice weigh significantly less than control littermates. Moreover, knockout mice are protected from diet-induced obesity and gain significantly less weight than littermate controls when placed on a high-fat diet. While food intake did not differ significantly between Kv1.3(-/-) and controls, basal metabolic rate, measured at rest by indirect calorimetry, was significantly higher in knockout animals. These data indicate that Kv1.3 channels may participate in the pathways that regulate body weight and that channel inhibition increases basal metabolic rate.

The identification of new targets for obesity therapeutics represents a key priority for the pharmaceutical industry. This has been driven by the large and growing numbers of obese individuals around the world, the high incidence of serious co-morbidities such as insulin resistance and diabetes, and a market predicted to reach $3.7 billion by 2008.

Obesity occurs when calorific intake exceeds energy expenditure. LeadDiscovery has recently analyzed two emerging anti-obesity targets, ghrelin which regulates food intake (click here for more), and the retinoids which also play a role in both food intake as well as energy expenditure (click here for more). The present study suggests that Kv1.3 channel blockers should be added to the list of drug discovery targets in the context of obesity. Of interest LeadDiscovery has recently featured a highly targeted library of candidate potassium channel modulators and screening this library may therefore yield highly attractive leads anti-obesity treatments (details on the library).

Adapted from Xu et al, Hum Mol Genet 2003 Mar 1;12(5):551-9

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk