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Highlights From The Literature

Edited by Christopher D. Verrico

Mg²⁺ enhances voltage sensor/gate coupling in BK channels. Horrigan FT, Ma Z. J Gen Physiol 131: 13–32, 2008.[CrossRef][Web of Science][Medline]

Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu

Question: Do Mg²⁺ and Ca²⁺ work through functionally similar mechanisms to activate BK channels?

Background: BK channels are large conductance Ca²⁺ and voltage-activated K⁺ channels, which allow K⁺ to leave the cytoplasm and promote membrane hyperpolarization under physiological conditions when activated by membrane potential and/or intra-cellular Ca²⁺. In addition to these two primary signals, BK channels are also sensitive to a number of regulatory ligands, including intracellular Mg²⁺. Previous studies suggest that Mg²⁺ and Ca²⁺ might work through functionally similar but independent mechanisms. This study examined the functional interaction between Mg²⁺- and voltage-dependent activation of BK channels.

Observations: Horrigan and Ma determined that the mechanism of Mg²⁺ action on BK channels is dependent on voltage sensor activation. They demonstrated that, when Mg²⁺ binds, it strengthens the allosteric coupling of voltage sensor activation to channel opening.

Significance: These findings imply that intracellular Mg²⁺ activates BK channels through a fundamentally different mechanism from Ca²⁺. Intracellular Ca²⁺ promotes channel opening independent of voltage sensor activation. In contrast, intracellular Mg²⁺ has effects on opening and voltage sensor activation that are interdependent. In fact, the primary effect of Mg²⁺ on gating is to enhance voltage sensor/gate coupling such that open activated states are stabilized. Given that BK channels are important for the function of nerve, muscle, and secretory cells, these findings may have relevance to a number of physiologists.

Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic β cells. Illies C, Gromada J, Fiume R, Leibiger B, Yu J, Juhl K, Yang SN, Barma DK, Falck JR, Saiardi A, Barker CJ, Berggren PO. Science 318: 1299–1302, 2007.[Abstract/Free Full Text]

Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: Does the inositol pyrophosphate IP7 contribute to the exocytotic capacity of pancreatic β-cells?

Background: Secretory granules containing insulin are divided into two distinct functional pools. One is a readily releasable pool that can undergo exocytosis when the cell is stimulated. A second reserve pool is located in the cytoplasm, which replenishes the readily releasable pool. The inositol pyrophosphate derivative IP7 is a high-energy phosphate group that has the ability to phosphorylate a subset of proteins in an ATP- and enzyme-independent manner. Phosphorylated inositol compounds are known to regulate insulin release from β-pancreatic cells; however, the underlying molecular mechanisms and physiological targets of the highly phosphorylated inositol polyphosphates are unknown.

Observations: Illies et al. show that pancreatic β-cells have high basal concentrations of IP7 and that an increase in IP7 concentration increases the size of the readily releasable pool of insulin-containing granules, leading to enhanced exocytosis. They also determined that inositol hexakisphosphate kinase 1 (IP6K1) is the critical endogenous kinase that generates IP7, allowing exocytosis to occur.

Significance: These findings address a key feature of impaired insulin release in diabetes because the readily releasable pool is essential for the first phase of insulin release, and a reduction in this pool correlates with a decrease in first-phase insulin release. Although the mechanism by which IP7 controls insulin release remains tentative, this lays the groundwork for future studies aimed at understanding insulin secretion. Finally, because IP7 is present in many other cell types, these findings could be important for understanding its physiological function in other secretory cells.

High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. Science 318: 1258–1265, 2007.[Abstract/Free Full Text]

GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK. Science 318: 1265–1273, 2007.

Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: What insight can be gained by determining the crystal structure of the β₂-adrenergic receptor (β₂-AR)?

Background: G-protein-coupled receptors (GPCRs) are a large protein family of trans-membrane receptors that, in response to extracellular ligand binding, activate signal transduction pathways and, ultimately, cellular responses. The structure of rhodopsin, a GPCR found in the eye, has been determined, but crystallizing other GPCRs has been challenging since many GPCRs, unlike rhodopsin, have an inherent conformational plasticity. In fact, this property may account for the ability of different ligands to induce a wide range of physiological effects.

Observations: In these tandem reports, the authors made several modifications to the β₂-AR and describe the structure of the β₂-AR bound to carazolol. The first describes a high-resolution chimera with a small globular protein (T4 lysozyme, T4L) inserted into the third intracellular loop, which reduced conformational heterogeneity and facilitated crystal nucleation. The second describes the design and functional characterization of the β₂-AR-T4L protein, as well as analyzing the structure in the context of existing mutagenesis data.

Significance: Although a full understanding of the structural basis of GPCR activation will require determining the different conformational states of the receptor and how they transduce signals, these findings are an important first step toward increasing our understanding of how GPCRs operate. The significance of this work is further underscored by the fact that GPCRs are involved in many diseases and are the target of around half of all modern medicinal drugs. Thus these findings will probably be applicable to other GPCRs and facilitate the design of new drugs with fewer side effects. It is noteworthy that, in a third paper (Rasmussen et al. Nature 450: 383–387, 2008), the authors present a lower resolution structure of the unmodified human β₂-AR in complex with an antibody fragment. The two structures together provide the most accurate picture of the β-AR structure to date.

Mechanisms of breathing instability in patients with obstructive sleep apnea. Younes M, Ostrowski M, Atkar R, Laprairie J, Siemens A, Hanly P. J Appl Physiol 103: 1929–1941, 2007.[Abstract/Free Full Text]

Nominated by Jerry Dempsey
Editor, Journal of Applied Physiology
University of Wisconsin
jdempsey{at}wisc.edu

Question: Why do patients with obstructive sleep apnea (OSA) have recurrent obstructions with arousal?

Background: In OSA, breathing during sleep is interrupted repeatedly by a physical block to airflow despite effort. At the end of an obstructive apnea, there is usually an abrupt increase in flow that is almost always associated with cortical arousal. In fact, it has been hypothesized that arousal is the mechanism responsible for opening of the airway. However, Younes et al. recently proposed that airway opening can occur independently of arousal. If the airway can open without arousal, why then do patients have recurrent obstructions with arousal?

Observations: In this report, Younes et al. set out to measure three responses that can result in instability in the setting of narrowed airway: 1) gain of the dynamic ventilatory response to CO₂ and hypoxia; 2) the increase in respiratory drive required for arousal (arousal threshold); 3) the increase in drive required for opening the airway reflexively without arousal (effective recruitment threshold). They confirmed that, in the majority of patients with severe OSA, increases in the chemical drive can result in opening of the upper airway without arousal. Arousals occur because the arousal threshold is crossed inadvertently by a fast-increasing respiratory drive. The important finding, however, was that the mechanism responsible for breathing instability varies considerably among patients.

Significance: That the mechanism responsible for breathing instability in patients with OSA may vary considerably explains why other studies that attempted to treat this condition by nonmechanical means (i.e., not involving surgery or pressure therapy) have produced inconsistent results. Therefore, in future studies when control of breathing is modified through nonmechanical interventions, it should be done selectively in patients based on the mechanism responsible for their breathing instability.

Species differences in Cl^– affinity and in electrogenicity of SLC26A6-mediated oxalate/Cl^– exchange correlate with the distinct human and mouse susceptibilities to nephrolithiasis. Clark JS, Vandorpe DH, Chernova MN, Heneghan JF, Stewart AK, Alper SL. J Physiol (January 3, 2008); doi:10.1113/jphysiol.143222.2007.

Nominated by Hugh Matthews
Senior Editor, The Journal of Physiology
hrm1{at}cam.ac.uk

Question: Can species differences in SLC26A6 oxalate/anion exchange properties account for the distinct susceptibilities of humans and mice to kidney stones?

Background: Kidney stones are most commonly composed of calcium oxalate crystals. Although control of oxalate intake has been a standard for attempting to control nephrolithiasis (the presence of kidney stones), recent studies have demonstrated a minimal impact of dietary oxalate on the frequency of kidney stone formation. Interestingly, mice are refractory to lithogenic agents, but recent findings identified slc26a6 as an oxalate nephrolithiasis gene in the mouse. Thus, in this study, differences in SLC26A6 oxalate/anion exchange properties were investigated between mice and humans.

Observations: Clark et al. determined that the human SLC26A6 mediates rates of oxalate/Cl^–exchange similar to the mouse. However, although both the human and mouse transporters exhibit highly cooperative dependence of oxalate efflux rate on extracellular Cl^– , the human K_1/2 for extracellular Cl^– is 62 mM whereas the mouse is only 8 mM. Additionally, whereas the mouse slc26a6 mediates bidirectional electrogenic oxalate/Cl^– exchange, human SLC26A6-mediated oxalate transport is electroneutral.

Significance: These data suggest that the substantial differences in amino acid sequence between the human and mouse transporters might underlie the different susceptibilities of these two species to kidney stone formation. In fact, the authors hypothesize that humans may be more susceptible to nephrolithiasis because of the low extracellular affinity and electroneutrality of oxalate efflux by human SLC26A6. As such, SLC26A6 may be an important therapeutic target to treat hyperoxaluria (excessive urinary excretion of oxalate).

Spike timing-dependent plasticity: a learning rule for dendritic integration in rat CA1 pyramidal neurons. Campanac E, Debanne D. J Physiol 586: 779–793, 2007.[CrossRef][Web of Science][Medline]

Nominated by Chris McBain
Senior Editor, The Journal of Physiology
mcbainc{at}mail.nih.gov

Question: Does the spike timing-dependent plasticity (STDP) rule apply to dendritic integration?

Background: In the hippocampus, long-term plasticity of dendritic integration involves long-term synaptic potentiation (LTP) becoming associated with enhanced firing probability of the postsynaptic neuron in response to a given excitatory synaptic input. In synaptic plasticity, temporally correlated pre- and postsynaptic spiking activity leads to the induction of LTP. STDP describes the functional changes in neurons and synapses that are sensitive to the timing of action potentials and thus accounts for long-term changes in synaptic plasticity. However, whether the STDP rule accounts for long-term changes in dendritic integration is unclear.

Observations: Campanac and Debanne demonstrate that the STDP rule is also valid for the plasticity of dendritic integration in CA1 pyramidal neurons. Although positively correlated pre- and postsynaptic activity induced LTP and facilitated dendritic integration, negatively correlated activity induced LTD and depressed dendritic integration. These effects were delay and NMDA receptor dependent. Finally, these modifications were not caused by changes in the balance between synaptic excitation and inhibition; instead, they were caused by modifying the activity of voltage-gated channels.

Significance: The STDP rule that states synapses increase their efficacy if the presynaptic neuron is activated momentarily before the postsynaptic neuron is activated can now be applied, not only to synaptic transmission, but also to dendritic integration. The authors speculate that the synergistic modifications in dendritic integration observed after LTP or LTD induction could be a functional redundancy to ensure significant changes in neuronal output when synaptic plasticity is induced.

IP₃ receptor-dependent Ca²⁺ release modulates excitation-contraction coupling in rabbit ventricular myocytes. Domeier TL, Zima AV, Maxwell JT, Huke S, Mignery GA, Blatter LA. Am J Physiol Heart Circ Physiol 29: H596–H604, 2008.

Nominated by Alberto Nasjletti
Editor, American Journal of Physiology—Heart and Circulation Physiology
New York Medical Center
alberto_nasjletti{at}nymc.edu

Question: Does inositol 1,4,5-triphosphate receptor (IP₃R)-dependent Ca ²⁺ signaling modulate excitation-contraction coupling (ECC) in ventricular myocytes?

Background: ECC, the physiological process of converting an electrical stimulus to a mechanical response, occurs in the heart via Ca²⁺-induced Ca²⁺ release. Thus Ca²⁺ enters through voltage-gated (L-type) Ca²⁺ channels, which triggers release of sarcoplasmic reticulum (SR) Ca²⁺ through ryanodine receptors (RyRs). The IP₃R-dependent Ca²⁺ release channel is expressed in cardiac myocytes, where it is thought to modulate ECC. Although there is little evidence for IP₃R-dependent Ca²⁺ release in ventricles, recent findings suggest that this signaling pathway may exert positive inotropic and arrhythmogenic effects during ventricular ECC.

Observations: Domeier et al. hypothesized that IP₃R-dependent Ca²⁺ signaling facilitates SR Ca²⁺ release during ECC in ventricular myocytes isolated from rabbit hearts. They determined that both type 2 and type 3 IP₃Rs are expressed in ventricular myocytes but at levels ~3.5-fold less than atrial myocytes. They also found that IP₃Rs facilitate SR Ca²⁺ release through RyR release clusters, which enhances the Ca²⁺ transient during ECC.

Significance: These results suggest that there is IP₃R-dependent Ca ²⁺ release in ventricular myocytes, which has positive inotropic effects on ECC by facilitating Ca²⁺ release through RyR clusters. These findings may have relevance to understanding some pathological conditions, since alterations in cardiac IP₃R-dependent signaling have been reported in obesity, during ischemia-reperfusion, and in heart failure.

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