Capturing Ion Channel Gating

This is a golden age for ion channels: a time when chemistry, molecular biology, and electrophysiology have come together with structural biology to provide glimpses into some truly amazing membrane proteins. And yet, as usual, the answers yield more questions. Is a new structure the structure of an open channel or of a closed one? How does the voltage sensor actually move? Though providing amazing insights, each crystal structure is just a still life portrait of the ion channel–it doesn't breathe or flicker; it has lost the " soul " that was deduced by electrophysiology. In a real sense, therefore, new structures serve as a starting point for more functional studies, rather than as an end point. Indeed, in this issue, Craven and Zagotta (2004) use functional studies to interpret structural information and enhance our understanding of the gating mechanisms of cyclic nucleotide-regulated channels. Craven and Zagotta chose to study the bovine retinal CNGA1 channel and the mouse HCN2 channel. CNGA1 is a cyclic nucleotide-gated channel that mediates the light response in retinal rod cells and has very little voltage dependence (for review see Kaupp and Seifert, 2002; Matulef and Zagotta, 2003). The channel is open in the dark, when cyclic GMP is high, and closes in the light, following hydrolysis of cyclic GMP via a G-protein cascade (for review see This channel is mainly activated by hyperpolarizing voltages, giving rise to the " h-current " (variously called I h , I f , or I q); the binding of cyclic nucleotides (usually cyclic AMP) shifts its voltage activation curve to less hyperpolarized potentials. Both channels exist as tetramers, and each channel has a cyclic nucleotide binding domain (CNBD) on the cytoplasmic COOH-terminal tail of each of its subunits. The COOH-terminal tails are thought to be involved in intersubunit interactions within cyclic nucleotide-regulated channels. For example, the C-helix portion of the rod channel CNBD appears to form intersubunit disulfide bonds mainly in closed states of the channel, and the C-helices are thought to disconnect and separate during channel opening (Matulef and Zagotta, 2002; Mazzolini et al., 2002). The C-linker regions of neighboring subunits also have been found to form disulfide bonds (Rosenbaum and Gordon, 2002). Furthermore, modulation of the channel by transition metal divalent cations appears to involve coordination of the metal ions by histidines on adjacent subunits (for review see Matulef and Zagotta, 2003). Finally, inhibition of cyclic nucleotide-gated …