Multiple Facets of Maxi-K+ Channels

In the classic era of electrophysiology, two distinct classes of ion channels were thought to exist in cell membranes: one class accounted for the generation of action potentials and their propagation along nerve fibers (voltage-gated channels); the other class accounted for the electrical signals at the chemical synapses (transmitter-gated channels). The advances made for the last decades in terms of elucidating the structure and function of ion channels show how simplistic this view was. Several hundreds of ion channel types, encoded by dozens of gene families expressed in all tissues, are known to be gated by elaborate processes related not only to membrane voltage changes or transmitter release but also to membrane deformation, direct coupling to G proteins, or the presence of intracellular ligands such as Ca 2 , H , nucleotides, and lipids, among others. In addition, in most channels, gating and/or ion permeation are modulated by phosphorylation, redox modification, nitrosylation, and even by gaseous oxygen and carbon monoxide. Ion channels do not work on isolation; they are intimately involved in most signaling pathways and their function is finely tuned by the metabolic state of the cells. The maxi-K , or BK, channel offers a most enticing example of the multifaceted nature of how ion channel function is regulated. These channels are highly sophisticated molecular machines, gated synergistically by voltage and Ca 2 , that exhibit both a high K selectivity and a large single-channel conductance. Each maxi-K channel is formed by four -subunits and up to four auxiliary -subunits (Atkinson et al., 1991; Vergara et al., 1998). The maxi-K channel -subunit is encoded by a single gene (Slo1) with several spliced isoforms, which are expressed rather ubiquitously. Each -subunit has seven transmembrane segments (S0–S6), which, like other voltage-gated K channel -subunits, provide the voltage sensor and pore domains, a small extracellular amino terminus, and an expanded cytosolic carboxyl terminus containing two regulators of K conductance (RCK) domains separated by a large nonconserved linker (Meera et al., 1997; Jiang et al., 2002). Several highand low-affinity Ca 2 binding sites on the COOH terminus confer upon maxi-K channels Ca 2 (and to a less extent Mg 2 ) sensitivity (Zeng et al., 2005). Depolarization and Ca 2 serve as allosteric regulators of channel activation by independently altering the energetics of channel opening (see below). This dual regulation by two physiologically relevant variables allows maxi-K channels to display a remarkable diversity in their properties among different cells and tissues and to participate in multiple cellular processes. Maxi-K channels play a fundamental role in the control of membrane potential and cellular excitability. In some cases, as with smooth muscle contraction and exocytosis, maxi-K channel–mediated hyperpolarization acts as a negative feedback mechanism, which decreases further Ca 2 entry through voltage-gated Ca 2 channels. Functional diversity among maxi-K channels also results from the selective tissue distribution of several types of auxiliary -subunits, which modulate important aspects of channel function. For example, the 1 subunit appears to mediate the regulation of maxi-K channels by estrogens (Valverde et al., 1999) and increases the sensitivity of the -subunit to Ca 2 . Other -subunits contain a large intracellular domain that can interact with the internal mouth of the pore to produce N-type inactivation (Wallner et al., 1999). Among the numerous intracellular signals modulating maxi-K channel function, H 2 O 2 , CO, NO, and O 2 have received special attention due to their possible participation in specialized homeostatic processes or in the pathophysiology of disease (Bolotina et al., 1994; Wang and Wu, 1997; López-Barneo et al., 2001; Tang et al., 2004; Williams et al., 2004). Yet, although the many facets of maxi-K channels have already been explored to some degree, there is room for surprises. Recently, it has been reported that the Slo1 channel possesses a conserved heme binding sequence motif (Wood and Vogeli, 1997; Tang et al., 2003) in the linker between the two RCK domains and that free intracellular heme markedly decreases the frequency of channel opening (Tang et al., 2003). In this issue of The Journal of General Physiology , Horrigan and colleagues (Horrigan et al.,