The impact of housing and high-fructose diet on behavior and cardiovascular response to eucalyptus wildfire smoke in WKY rats.

Genetic variants that affect the function of K2P K channels are now increasingly associated with a range of diseases, including diabetes, nephropathy, migraine, sleep apnea, hypertension, and other cardiac disorders, as well as a range of neurodevelopmental disorders (). However, despite the pressing need, there are few effective treatments for these complex conditions, and their underlying mechanisms are often not well understood. K2P channels represent a structurally distinct subfamily of K channels. In addition to their distinct extracellular Cap domain, each subunit contains four transmembrane helices (M1–M4) and two pore domains (P1 and P2). Two subunits therefore assemble as a “dimer of dimers” to create a pseudotetrameric channel that is similar to other classical K channel pores (; ). There are 15 different human K2P () channels, and members of this subfamily of K channels are often referred to as simple “leak” conductances involved in establishing the resting membrane potential, but it is now clear they exhibit complex patterns of dynamic regulation by diverse stimuli, including many G-protein–coupled receptor (GPCR)-associated regulatory pathways (; ). Understanding K2P channel dysfunction in the disease state is therefore critical for a clearer insight into these rare channelopathies and to exploit the therapeutic potential of K2P channels in other more common disease states (; ). and encode the TASK-1 and TASK-3 K2P channels, respectively. Although separate genes with distinct tissue-specific patterns of expression, they share almost 80% amino acid identity within the main pore-forming transmembrane regions (). Consequently, they exhibit significant structural and functional similarity (; ; ), and in those cell types where they are coexpressed, they can co-assemble into heteromeric TASK-1/TASK-3 channels, which possess distinct functional properties (; ; ; ).