Controlling potassium channel activities: Interplay between the membrane and intracellular factors

Neural signaling is based on the regulated timing and extent of channel ope ning; therefore, it is important to understand how ion channels open and cl ose in response to neurotransmitters and intracellular messengers. Here, we examine this question for potassium channels, an extraordinarily diverse g roup of ion channels. Voltage-gated potassium (Kv) channels control action- potential waveforms and neuronal firing patterns by opening and closing in response to membrane-potential changes. These effects can be strongly modul ated by cytoplasmic factors such as kinases, phosphatases, and small GTPase s. A Kv a subunit contains six transmembrane segments, including an intrins ic voltage sensor. In contrast, inwardly rectifying potassium (Kir) channel s have just two transmembrane segments in each of its four pore-lining a su bunits. A variety of intracellular second messengers mediate transmitter an d metabolic regulation of Kir channels. For example, Kir3 (GIRK) channels o pen on binding to the G protein beta gamma subunits, thereby mediating slow inhibitory postsynaptic potentials in the brain. Our structure-based funct ional analysis on the cytoplasmic N-terminal tetramerization domain T1 of t he voltage-gated channel, Kv1.2, uncovered a new function for this domain, modulation of voltage gating, and suggested a possible means of communicati on between second messenger pathways and Kv channels. A yeast screen for ac tive Kir3.2 channels subjected to random mutagenesis has identified residue s in the transmembrane segments that are crucial for controlling the openin g of Kir3.2 channels. The identification of structural elements involved in potassium channel gating in these systems highlights principles that may b e important in the regulation of other types of channels.