Focus Issue: Tuning in to the Ion Channel

Robert Hooke, who noted the resemblance of the small compartments visible in a slice of cork viewed through a compound microscope to the little rooms occupied by monks, was the first person to observe that most basic structural feature of all cells—the division into cell interior and exterior. The separation by a hydrophobic plasma membrane of a cell interior of different ionic composition from the extracellular environment—and the existence of membrane-bound organelles with their own specific internal milieus—necessitated mechanisms to facilitate ion movement among these different compartments. Indeed, the crucial importance to cellular function of conduits that enable the transmembrane movement of ions and water was underlined by the award of the 2003 Nobel Prize in Chemistry to Peter Agre "for the discovery of water channels" and Roderick MacKinnon "for structural and mechanistic studies of ion channels." The activity of ion channels, membrane-spanning proteins that provide rapid pathways for ion transit across the plasma membrane and intracellular membranes, can be modulated by various cell signals to either facilitate or prevent the transmembrane flux of particular ionic species. This regulated ionic movement can then be exploited to transmit electrical or chemical signals or to alter the ionic composition of a particular cellular compartment and thereby affect its function. Recognizing the critical interplay between ion channel activity and cell signaling, Science’s STKE has published a series of individual articles and thematic Focus Issues on various aspects of the regulation and function of different classes of ion channels.

The first STKE Focus Issue on ion channels, "Ion Channels—Opening the Gateless Gate," concentrated on gating—the changes in protein conformation that open or shut the channel in response to some specific signal. The Focus Issue on channel gating included three articles: a Review by Armstrong on voltage-gated potassium channels (a prototype of voltage-gated ion channels); a Review by Auerbach on the transition state between the closed and the open conformations of the nicotinic acetylcholine receptor (a prototype of the pentameric family of ligand-gated ion channels); and a Perspective by Chen on the relationship between chloride permeation and fast gating in ClC chloride channels. A comprehensive Review on mechanically gated channels by Sukharev and Corey, in which the authors covered both the paradigm of channels gated by force conveyed through tethering to the cytoskeleton and that of channels gated by stress conveyed through tension in the cell membrane, continued the gating theme.

This week, Science’s STKE presents a second Focus Issue on ion channels, in which we shift the emphasis from channel gating to the interrelated themes of channel function and how channel activity is influenced by metabolic state and the concentrations of various intracellular molecules.

The Review by Faundez and Hartzell concerns the functions of intracellular chloride channels in endosomes and related organelles. The authors describe how chloride influx into endosomes modulates lumenal pH of the endosomes by shunting the membrane potential generated by proton pumps. The authors discuss how lumenal pH—and perhaps lumenal chloride concentration itself—affects membrane trafficking and present an intriguing scenario whereby the activity of chloride channels in the membranes of synaptic vesicles could act to influence the neurotransmitter content of such vesicles. An accompanying animation depicts how lumenal pH and chloride concentration change at different stages of the endosomal pathway.

H⁺ flux and pH also have roles in cellular responses to invading organisms. Phagocytes—such as macrophages and neutrophils—engulf and destroy harmful microorganisms, a process characterized by the "respiratory burst." During the respiratory burst, the NADPH oxidase enzyme complex ejects electrons into the phagosome (or into the extracellular fluid) to reduce extracellular oxygen to superoxide anion, which is a precursor to various reactive oxygen species (ROS). Traditionally, H⁺ flux through proton channels has been thought to compensate for the charge carried by this electron current and the ROS generated during the respiratory burst have been believed to play a key role in destroying the captured microbes. In a Perspective on the functions of ion channels in phagocytes, DeCoursey critically discusses recent research that challenges this view and suggests that K⁺ flux through large conductance calcium- and voltage-activated potassium channels (known as maxi-K, Slo1, or BK channels) and the ensuing increase in phagosomal pH and osmolarity—which activate proteolytic enzymes—are the critical factors in bacterial destruction. Readers can learn more about maxi-K channels in a Perspective by Rothberg in the STKE Archives on the 50-state dual allosteric model of large conductance calcium- and voltage-activated potassium channel gating.

The topic of how changes in metabolic state can influence potassium channel activity is discussed in a Perspective by Trauner and Kramer. One example concerns recent research suggesting that heme, which can be released from hemoproteins in response to cell injury, hypoxia, or stress, may serve as a physiological inhibitor of large conductance calcium- and voltage-activated potassium channel function. Peroxide, a ROS produced during periods of high cellular activity, activates inward-rectifying ATP-sensitive K⁺ channels (K_ATP channels), a class of channels already known for coupling metabolic state to excitability to regulate insulin release. Perhaps most intriguing of all, the β subunits of some voltage-gated potassium channels have been found to bind NADP—suggesting a direct mechanism for linking metabolic state to channel function (and thus membrane excitability). Thus, regulation of K channel function by metabolic state appears common to various classes of K channels, and Trauner and Kramer predict that other K channels will be found to be similarly regulated.

The themes of ion channel function and how channels are influenced by changes in the internal milieu draw closest together when ions themselves act as signaling molecules to regulate channel function. The activation of large conductance calcium- and voltage-activated potassium channels by calcium provides one example of this. In a Perspective from the STKE Archives, Mirshahi et al. discuss direct and indirect mechanisms through which sodium may act and indirect mechanisms through which chloride may act to regulate the activity of heterotrimeric GTP-binding protein (G protein)-activated inwardly rectifying K⁺ (GIRK or Kir3) channels. An intriguing example of ion-regulated ion channel function is provided by Wolf in a Perspective on the emerging role of TRPM7 in cellular magnesium homeostasis. TRPM7, a member of the melastatin subfamily of the transient receptor potential family of ion channels, facilitates the influx of magnesium into the cell and the efflux of monovalent cations. Recent research indicates that TRPM7 activity may itself be regulated by intracellular magnesium concentration, providing a negative feedback mechanism to maintain magnesium homeostasis. Members of the TRPM channel subfamily have the unusual ability to act as enzymes as well as channels, a property that enables them to directly participate in intracellular signaling pathways. At present, the TRPM channels, which are discussed along with other TRP-family channels in a Review by Montell from the STKE Archives, are the only known "chanzymes." However, the resemblance of the NADP-binding site of the β subunit of certain potassium channels to the active site of the enzyme aldose reductase suggests that they may in fact act as an oxidoreductase and that the list of chanzymes–and the known direct involvement of channels in intracellular signaling pathways–may thus continue to grow.

Featured in This Focus Issue

Reviews

• V. Faundez, H. C. Hartzell, Intracellular chloride channels: Determinants of function in the endosomal pathway. Sci. STKE 2004, re8 (2004). [Gloss] [Abstract] [Full Text] [Animation]

Perspectives

• T. E. DeCoursey, During the respiratory burst, do phagocytes need proton channels or potassium channels, or both? Sci. STKE 2004, pe21 (2004). [Summary] [Full Text]

• D. Trauner, R. H. Kramer, Metabolic modulation of potassium channels. Sci. STKE 2004, pe22 (2004). [Summary] [Full Text]

• F. I. Wolf, TRPM7: Channeling the future of cellular magnesium homeostasis? Sci. STKE 2004, pe23 (2004). [Summary] [Full Text]

Related Resources

Editorial Guides

• E. M. Adler, N. R. Gough, L. B. Ray, Focus Issue: Ion channels—Opening the gateless gate. Sci. STKE 2003, eg9 (2003). [Full Text]

Reviews

• C. M. Armstrong, Voltage-gated K channels. Sci. STKE 2003, re10 (2003). [Gloss] [Abstract] [Full Text]

• A. Auerbach, Life at the top: The transition state of AChR gating. Sci. STKE 2003, re11 (2003). [Gloss] [Abstract] [Full Text] [Animation]

• S. Sukharev, D. P. Corey, Mechanosensitive channels: Multiplicity of families and gating paradigms. Sci. STKE 2004, re4 (2004). [Gloss] [Abstract] [Full Text]

• C. Montell, Physiology, phylogeny, and functions of the TRP superfamily of cation channels. Sci. STKE 2001, re1 (2001). [Gloss] [Abstract] [Full Text]

Perspectives

• T.-Y. Chen, Coupling gating with ion permeation in ClC channels. Sci. STKE 2003 (188), pe23 (2003). [Summary] [Full Text]

• T. Mirshahi, T. Jin, D. E. Logothetis, Gßγ and K_ACh: Old story, new insights. Sci. STKE 2003 (194), pe32 (2003). [Summary] [Full Text]

• B. S. Rothberg, Allosteric modulation of ion channels: The case of maxi-K Sci. STKE 2004, pe16 (2004). [Summary] [Full Text]

ST on the Web

• Educator Sites (http://stke.sciencemag.org/cgi/ul/sigtransUl;CAT_9) featuring the Nobel Prize in Chemistry 2003.

Events

• Gordon Research Conferences: Ion Channels, 11 to 16 July 2004 [Details and Events Calendar]