Cellular excitability is modulated by the precise function of voltage-sensitive ion channels. Large conductance potassium channels (Maxi-K) are unique in that they are sensitive to transmembrane potential and intracellular Ca2+ concentrations. These channels, important for neuronal firing and vascular tone, share many features with voltage-dependent Na+, Ca2+, and K+ channels. Among these are the S4 region, a motif with a repeated triple sequence of one positively charged amino acid and two hydrophobic amino acids. This region is thought to be the voltage sensor. Maxi-K is subject to complex metabolic control control that also involves G proteins and phosphorylation/dephosphorylation reactions. This type of K+ channel is composed of two subunits, the pore-forming α subunit (hslo) and the regulatory β subunit. The α subunit is subject to direct phosphorylation by cyclic GMP-dependent protein kinase (PKG) and dephosphorylation by protein phosphatase 2A. The fact that the α subunit of Maxi-K channels is a substrate of PKG supports the idea that these channels perform an important function in the cellular response to potent vasodilators, such as nitrocompounds and atrial natiuretic peptide.