Subtype specific responses in hKv7.4 and hKv7.5 channels to polyunsaturated fatty acids

The KV7.4 and KV7.5 subtypes of voltage-gated potassium channels are expressed in several tissues where they play a role in physiological processes such as sound amplification in the cochlea and adjusting vascular smooth muscle tone. Therefore, the mechanisms that regulate KV7.4 and KV7.5 channel function are of interest. Here, we study the effect of polyunsaturated fatty acids (PUFAs) on human KV7.4 and KV7.5 channels expressed in Xenopus oocytes. We report that KV7.5 is activated by PUFAs, which shift the V50 of the conductance versus voltage (G(V)) curve towards more negative voltages. This response depends on the charge of the head group as an uncharged PUFA analogue has no effect and a positively charged PUFA analogue induces positive V50 shifts. In contrast, we find that the KV7.4 channel is inhibited by PUFAs, which shift V50 towards more positive voltages. No effect on V50 of KV7.4 is observed by an uncharged or a positively charged PUFA analogue. Oocytes co-expressing KV7.4 and KV7.5 display an intermediate response to PUFAs. Altogether, the KV7.5 channel's response to PUFAs is like that previously observed in KV7.1-7.3 channels, whereas the KV7.4 channel response is opposite, revealing subtype specific responses to PUFAs.

Ion channels as convergence points in the pathology of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a fatal disease of the cardiopulmonary system that lacks curative treatments. The main pathological event in PAH is elevated vascular resistance in the pulmonary circulation, caused by abnormal vasoconstriction and vascular remodelling. Ion channels are key determinants of vascular smooth muscle tone and homeostasis, and four PAH channelopathies (KCNK3, ABCC8, KCNA5, TRPC6) have been identified so far. However, the contribution of ion channels in other forms of PAH, which account for the majority of PAH patients, has been less well characterised. Here we reason that a variety of triggers of PAH (e.g. BMPR2 mutations, hypoxia, anorectic drugs) that impact channel function may contribute to the onset of the disease. We review the molecular mechanisms by which these ‘extrinsic’ factors converge on ion channels and provoke their dysregulation to promote the development of PAH. Ion channels of the pulmonary vasculature are therefore promising therapeutic targets because of the modulation they provide to both vasomotor tone and proliferation of arterial smooth muscle cells.

Arginine Therapy for Lung Diseases

Nitric oxide (NO) is produced by a family of isoenzymes, nitric oxide synthases (NOSs), which all utilize L-arginine as substrate. The production of NO in the lung and airways can play a number of roles during lung development, regulates airway and vascular smooth muscle tone, and is involved in inflammatory processes and host defense. Altered L-arginine/NO homeostasis, due to the accumulation of endogenous NOS inhibitors and competition for substrate with the arginase enzymes, has been found to play a role in various conditions affecting the lung and in pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, and bronchopulmonary dysplasia. Different therapeutic strategies to increase L-arginine levels or bioavailability are currently being explored in pre-clinical and clinical studies. These include supplementation of L-arginine or L-citrulline and inhibition of arginase.

The therapeutic agents that target ATP-sensitive potassium channels

ATP-sensitive potassium (KATP) channels are a major drug target for the treatment of type-2 diabetes. KATPchannels are ubiquitously expressed and link the metabolic state to electrical excitability. In pancreatic β-cells, KATPchannels are crucial in the regulation of glucose-induced insulin secretion. Also, KATPchannels are involved in the protection against neuronal seizures and ischaemic stress in the heart, brain and in the regulation of vascular smooth muscle tone. Functional KATPchannels are hetero-octamers composed of two subunits, a pore forming Kir6, which is a member of the inwardly rectifying potassium channels family, and a regulatory sulphonylurea receptor (SUR). In response to nucleotides and pharmaceutical agonists and antagonists, SUR allosterically regulates channel gating. The allosteric communication pathways between these two heterologus proteins in KATPchannels are still poorly understood. This review will highlight the therapeutic agents that target KATPchannels and are used to treat diabetes and cardiovascular diseases.