br The small conductance Ca activated K SKCa SK SKCa

The small conductance Ca-activated K+ (SKCa; SK, SKCa, KCa2) channels are recognized as a subfamily of KCa channels (Bond, Maylie, & Adelman, 1999). The SKCa channel is encoded by three distinct genes, KCNN1, KCNN2, and KCNN3 with different sensitivities toward apamin. Different with BKCa channels, SKCa channels are activated solely by internal Ca with higher sensitivity, submicromolar concentration, to induce hyperpolarization (Latorre, Oberhauser, Labarca, & Alvarez, 1989). SKCa channels are architected in a kind of tetramer form with four subunits, each of which contains six transmembrane hydrophobic alpha helical domains (S1–S6). Activated calmodulin, combined with calcium, binds to its binding domain on the intracellular subunits, results in opening of SKCa channels. Therefore, the channels function to integrate the intracellular Ca concentration into hyperpolarization of cell membrane. SKCa channels are considered to play a fundamental role in all excitable cells (Weatherall, Seutin, Liegeois, & Marrion, 2011). SKCa channels are first identified in the central nervous system with sensitivity toward a neurotoxin apamin (Kohler et al., 1996). The SKCa channels play pivotal roles in the nervous system, affecting the intrinsic excitability of neurons, the synaptic transmission, and also synaptic plasticity (Adelman et al., 2012, Bond et al., 1999, Bond et al., 2005). Additionally, it has been demonstrated that all three subtypes of SKCa channels are functionally expressed in human and mouse cardiac myocytes, highly expressed in atria over ventricular myocytes (Bond et al., 1999, Diness et al., 2010, Tuteja et al., 2005). SKCa channels are involved in membrane hyperpolarization and inhibition of SU 4312 sale firing in cardiovascular system as well as in neuron system.
Role of SKCa in Cardiovascular System
Perspective for SKCa Channels as Potential Target for Cardiovascular Diseases Blockade of SKCa channels has been suggested as a novel target for cognitive enhancement, depression, cardiac arrhythmias, and myotonic muscular dystrophy. In cardiovascular system, SK2 channel was evidenced to be involved in certain treatment for AF, such as in the treatment with spinal cord stimulation, inhibition of SK2 contributed to the therapeutic effect by inhibiting autonomic remodeling (Wang, Zhou, et al., 2015). The negative SK2 modulators were effective agents for AF and offered a promising new therapeutic opportunity in the treatment of AF (Christophersen and Wulff, 2015, Diness et al., 2010). However, blockade of SK channels was considered to be both antiarrhythmic and proarrhythmic, which is an open question for the future investigations. SK3 channels contribute to endothelium-dependent vessel relaxation, suggesting that these channels are potential targets for treatment of hypertension, pulmonary hypertension, and chronic obstructive pulmonary disease (Kroigaard et al., 2012).
Acknowledgment
Author Contributions: Y.L. Bai wrote the SKCa part, B.Z. Cai wrote the IKCa part, D.L. Dong wrote the BKCa part and organized the whole paper. Conflict of Interest: The authors declare no conflict of interest.
Introduction Calcium-activated K+ channels (KCa) transduce fluctuations in intracellular calcium concentration into changes of potassium permeability and of membrane potential in both excitable and nonexcitable cells. KCa channels are divided into three subfamilies: BKCa, IKCa and SKCa according to their big-, intermediate- and small-conductances, respectively [1]. These sub-types also differ in their amino acid sequences, pharmacological profiles and calcium sensitivities. IKca are involved in fundamental cellular responses, such as vasodilatory effects of bradykinin in the kidney [2], activation of brain capillary endothelial cells by endothelin [3], cell dehydration in sickle cell anemia [4], and activation of secondary immune responses [5]. IKCa channels of human erythrocytes are also called Gardos channels, they mediate the calcium-induced K+ efflux [6], which probably contributes to the elimination of senescent red blood cells [7]. The function of calcium-activated K+ permeability in human erythrocytes still remains poorly understood. Since Gardos channels have been used as a model to study the pathophysiology of myotonic dystrophy [8], a human systemic disease involving defective expression of myotonin protein kinase [9], [10], [11], it is important to elucidate the role of protein kinases in the modulation of these channels. The data available confirm that PKA is an important regulator of IKCa in general [12] and of Gardos channels in particular [13]. However, a detailed description of the role of PKC on single Gardos channels has not been reported [14], [15], [16], [17], [18]. The lack of information prompted us to study the effects of endogenous PKC activation or inhibition on the activity of single IKCa channels of human erythrocytes. Here we report a clear-cut PKC-dependent down-modulation of Gardos channel unitary currents in excised patches. We also provide evidence that PKC and PKA have antagonistic effects in determining the channel activity level.