Understanding the Cap Structure in K2P Channels

The two-pore domain potassium (K2P) channel family is composed by 15 members, identified in the human genome, and also K2P channels have been identified in yeast, plants, zebrafish, nematode and fruitfly (Goldstein et al., 2001). Based on their primary structure and functional properties, K2P channels are grouped into six distinct subfamilies K2P channels play several key roles in excitable cells. For instance, K2P channels generate the called leak or background currents that are responsible for the maintenance of the resting membrane potential close to the equilibrium potential of K + (E K) which sets the resting membrane potential below the firing threshold K2P channels have also been linked to several pathologies. For example, TASK-1 malfunction as consequence of missense mutations or its pharmacological inhibition has been associated to pulmonary hypertension (Ma et al., 2013) and cardiac arrhythmias (atrial fibrillation) (Schmidt et al., 2015), respectively. Additionally, mutations of TASK-3 (G236R) and TRESK are linked with the Birk Barel syndrome (Barel et al., 2008) and familial migraine (Lafreniere et al., 2010). On the other hand, an overexpression of TASK-3 has been found in some human breast cancer tumors where it has been proposed acts as a proto-oncogene (Mu et al., 2003). For comprehensive reviews see Enyedi and Czirjak (2010) and Feliciangeli et al. (2015). Taken together, K2P channels could be potential pharmacological targets for restoring the function of dysfunctional excitable tissues as well as in cancer treatment. The open probability of K2P channels is highly regulated by a wide variety of stimuli such as kinases, phosphatases, lipids, G proteins, internal and external pH, mechanical force, protein-protein interactions and volatile anesthetics K2P channels display a structure that markedly differs to that described for Kv and Kir K + channel families. Each K2P subunit consists of four transmembrane domains (M1-M4 domains), two pore forming domains (P domains) with both N-and C-termini facing the cytosolic side (Figure 1B). Given that 4 P domains are required to form a K + selectivity filter, it was assumed that the K2P channels must function as dimers. Strong evidence to support this architecture was initially reported (Lesage et al., 1996; Lopes et al., 2001) and then it was corroborated by crystallographic structures obtained from K2P members (Brohawn et al., 2012; Miller and Long, 2012) (see Figure 1F). Another particular feature of K2P channels is the so-called cap structure that is formed by the extracellular M1-P1 linkers of each K2P …