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Edited by Christopher D. Verrico
A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore.
Struyk AF, Cannon SC. J Gen Physiol 130: 11–20, 2007.
Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu
Question: Can a proton-selective gating pore in a Na+ channel account for the aberrant sarcolemmal depolarization observed in hypokalemic periodic paralysis (HypoPP)?
Background: HypoPP is an autosomal recessive disorder that is characterized by muscle weakness and/or paralysis accompanied by low serum potassium levels. The paralysis results from sustained depolarization of the sarcolemmal resting potential, which causes muscle fibers to be unexcitable. Mutations at positively charged residues in the S4 voltage-sensing, membrane-spanning segment of the ion channels CaV1.1 (L-type Ca2+ channel) and NaV1.4 (voltage-gated Na+ channel) have been linked to the disorder. Although these mutations alter the gating of both channels, they do not explain the sarcolemmal depolarization observed in the affected muscle.
Observations: Building on recent findings that suggest the mutations cause aberrant ionic leak conductance, Struyk and Cannon tested the gating-pore conductance of the rat isoform of NaV1.4 with the HypoPP mutation. They found that mutation of the S4 voltage sensor results in a hyperpolarization-activated current, which is conducted by protons through an accessory permeation pathway across the membrane. This conductance was selective for protons because larger ions, such as Na+, were unable to permeate the membrane via this pathway.
Significance: These results suggest that a mutation in the voltage-sensing domain of a Na+ channel results in the transport of protons. Although the magnitude of the proton leak is likely too small to fully account for the sarcolemmal depolarization observed in HypoPP, it may contribute to the instability of the membrane resting potential by interfering with intracellular pH homeostasis. However, it is possible that other alterations to normal physiology (e.g., an increase in myoplasmic Na+ caused by these gating pore currents) might be (or contribute to) the mechanism by which the mutation exerts its effect. Nonetheless, these findings may be relevant to the pathogenesis of HypoPP and the many other disorders that are characterized by mutations in voltage sensor domains.
Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis. Garcia-San Frutos M, Cacicedo L, Fernandez C, Vicent D, Velasco B, Zapatero H, Sanchez-Franco F. Am J Physiol Endocrinol Metab (August 7, 2007); 10.1152/ajpendo.00236.2007.
Nominated by Patricia Brubaker
Associate Editor, American Journal of Physiology—Endocrinology and Metabolism
University of Toronto
p.brubaker{at}utoronto.ca
Question: What is responsible for the age-related decline in growth hormone (GH) secretion?
Background: GH secretion by the somatotrope cells of the anterior pituitary gland declines progressively with aging, which results in lower serum insulin-like growth factor-1 (IGF-1) levels. There are several regulators of GH that can potentially cause this decline. The secretion of GH is stimulated by the neuropeptide GH-releasing hormone (GHRH) and the GH secretagogue ghrelin. In contrast, GH release is inhibited by somatostatin (SS) and IGF-1. Some studies suggest that a higher somatostatinergic tone is the mechanism that drives the age-related decline in GH. However, other studies suggest that the decline in GH might be related to decreased secretion of GHRH.
Observations: Garcia-San Frutos and colleagues sought to determine the mechanisms underlying the age-related decline in the GH/IGF-1 system. They found that GHRH mRNA, immunoreactive (IR) GHRH, SS mRNA, IR-SS, GH secretagogue receptor (GHS-R), and IGF-1 mRNA all decreased significantly in the hypothalamus and median eminence of old rats. In contrast, hypothalamic IGF-1 receptor mRNA and protein were not altered. Chronic treatment with GH-releasing hexapeptide (GHRP-6) normalized, at least in part, some of the indexes related to somatrotrophic function in old rats.
Significance: The present findings, which include analysis of most of the hypothalamic signals involved in the regulation of GH, suggest that the main mechanism underlying the decline in the GH/IGF-1 system is reduced GHRH secretion and not an increase in SS tone. Given the significance of GH actions on many physiological processes, these data may have relevance to the cognitive impairment, decreased neuroprotection or generalized catabolic state associated with aging.
Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNF
.
Manderson AP, Kay JG, Hammond LA, Brown DL, and Stow JL. J Cell Biol 178: 57–69, 2007.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: How are the cytokines, tumor necrosis factor- (TNF) and interleukin 6 (IL-6), trafficked following an immune response?
Background: TNF and IL-6 are cytokines that are secreted by macrophages in response to inflammation. Recently, the intracellular pathways responsible for TNF trafficking and secretion have been identified. IL-6, which unlike TNF lacks a transmembrane domain, is trafficked and secreted as a soluble protein. However, little is known regarding the intracellular trafficking of IL-6. Therefore, Manderson et al. sought to determine whether IL-6 is secreted via the same pathway as TNF and whether both of these cytokines rely on the same intracellular carrier and trafficking machinery.
Observations: Manderson et al. directly compared the trafficking and secretion of endogenous and fluorescently tagged TNF and IL-6 in macrophages. Newly synthesized IL-6 accumulates in the Golgi complex and exits in tubulovesicular carriers either alone or together with TNF. Upon leaving the Golgi complex, IL-6 is trafficked to the recycling endosome before it is delivered to the cell surface. When TNF and IL-6 are trafficked to the recycling endosome together, IL-6 is dynamically separated from TNF, which is ultimately delivered to phagocytic cups before being secreted across the plasma membrane.
Significance: These results reveal a new route for IL-6 trafficking. In fact, these findings highlight the importance of compartmentalization of IL-6 and TNF within the recycling endosome and the role these organelles play in orchestrating the differential secretion of the cytokines during macrophage immune responses. Understanding where the trafficking of these two cytokines diverges may be important for joint or separate targeting by drugs to treat chronic inflammatory conditions.
The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period.
Godinho SI, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O’Neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM. Science 316: 897–900, 2007.
SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins.
Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M. Science 316: 900–904, 2007.
Nominated by Michael Caplan
Associate Editor, Physiology
Yale University School of Medicine
michael.caplan{at}yale.edu
Question: Do F-box proteins play a role in maintaining circadian rhythms?
Background: Circadian rhythms are endogenously generated 24-h cycles that are important for determining the sleeping and feeding patterns of animals. In fact, brain wave activity, hormone production, cell regeneration, and other physiological activities are all linked to these cycles. In mammals, circadian cycles are generated and maintained by autoregulatory transcriptional and translational feedback loops. The transcription factors CLOCK and BMAL1 induce expression of the genes Period (Per) and Cryptochrome (Cry). Per and Cry protein products feedback onto CLOCK and BMAL1, inhibiting their further transcription. When the proteins CRY and PER degrade, transcription begins again.
Observations: In the first report, Godinho et al. perform a screen of mutagenized mice for abnormal circadian regulation and identify a mutation, "after-hours" (Afh), located in the gene Fbxl3. This gene codes for an F-box protein that was not previously known to be linked to the circadian cycle. The Afh mutant allele of this gene caused a longer circadian rhythm (~27 h). In the second study, Busino et al. identified CRY as an interactor of Fbxl3 using an unbiased screen. They then showed that Fbxl3 drives the ubiquitylation and consequent degradation of the clock protein CRY. The two groups also collaborated and showed that in Afh mutated mice CRY was degraded at a much slower rate, which could explain the longer circadian cycles.
Significance: This work provides direct in vivo evidence that CRY degradation via F-box proteins is an important regulatory mechanism involved in the circadian rhythm of mammals. The next step is to find the corresponding gene in humans. Once identified, these genes/proteins can become potential therapeutic targets as several disorders may be associated with disruptions in the sleep/wake cycle, such as dementia, bipolar disease, and mental retardation.
Proteoglycans fragmentation and respiratory mechanics in mechanically ventilated healthy rats. Moriondo A, Pelosi P, Passi A, Viola M, Marcozzi C, Severgnini P, Ottani V, Quaranta M, Negrini D. J Appl Physiol (June 14, 2007); 10.1152/jap-plphysiol.00056.2007.
Nominated by Jerry Dempsey
Editor, Journal of Applied Physiology
University of Wisconsin
jdempsey{at}wisc.edu
Question: Are proteoglycans (PGs) damaged by mechanical ventilation?
Background: In patients with respiratory failure, or during general anesthesia, mechanical ventilation is necessary to sustain respiratory function. However, this can be detrimental to lung parenchyma by increasing mechanical stress that can damage the endothelial and epithelial cells. To date, most investigations have sought to understand the damaging effects of mechanical ventilation on the alveolar-capillary layer. Few studies have explored the role of the macromolecular components of the extracellular tissue matrix (ECM), which is filled with PG macromolecules in which a core protein is covalently linked to glycosaminoglycan (GAG) chains.
Observations: Moriondo et al. investigated whether stretching of the lung tissue and/or positive alveolar pressure swings during mechanical ventilation has an effect on the composition and/or structure of the main pulmonary PG families. They determined that when normal breathing is shifted to mechanical ventilation it leads to marked fragmentation of the GAGs components of pulmonary extracellular PGs.
Significance: These studies suggest that mechanical ventilation severely affects the pulmonary extracellular architecture, which exposes the lung parenchyma to development of ventilator-induced injury. They also imply that monitoring of the respiratory mechanics and gas-exchange is not reliable to detect lung injury induced by a ventilator.
Evidence for gut factor in K+ homeostasis.
Lee FN, Oh G, McDonough AA, Youn JH. Am J Physiol Renal Physiol (May 23, 2007); 10.1152/ajprenal.00427.2006.
Nominated by Gerhard Giebisch
Special Advisor, Physiology
Yale University School of Medicine
gerhard.giebisch{at}yale.edu
Question: Is there a gut factor that senses K+ intake?
Background: Extracellular K+ homeostasis relies on the maintenance of total body K+ content, which is maintained by the kidneys by balancing dietary K+ intake and K+ excretion. Additionally, K+ homeostasis relies on distribution of K+ between intracellular and extracellular spaces, which is maintained primarily by the liver and skeletal muscle. Traditionally, maintenance of K+ homeostasis has been thought to function as a negative feedback control mechanism in which extracellular [K+] is the variable that is both sensed and regulated. However, recent findings suggest that K+ intake is sensed by K+ sensors in the gut, portal vein, and/or liver, which implies that a feed-forward mechanism is in control of K+ homeostasis.
Observations: Lee et al. tested the hypothesis that K+ intake is sensed by the gut, portal vein, and/or liver by infusing K+ into the stomach, the hepatic portal vein, or a systemic vein and measuring the impact on plasma [K+] and renal K+ excretion. During fasting, the infusions of K+ via different routes resulted in similar profiles of plasma [K+] and renal K+ excretion. However, when simultaneously fed a K+-deficient diet, the intragastric, but not the intraportal, K+ infusion enhanced the efficiency of renal K+ excretion and prevented rises in plasma [K+] during the K+ infusion.
Significance: These findings suggest that a gut factor does in fact sense K+ intake and that this sensor has a role in enhancing renal efficiency of K+ excretion during dietary K+ intake. This supports the concept that there are factors other than extracellular [K+] that regulate renal K+ excretion. Future efforts will likely be aimed at determining the mechanism by which K+ is sensed in the gut.
Mechanical influences on skeletal muscle vascular tone in humans: insight into contraction-induced rapid vasodilatation. Kirby BS, Carlson RE, Markwald RR, Voyles WF, Dinenno FA. J Physiol (May 10, 2007); 10.1113/jphysiol.131250.2007.
Nominated by Michael Joyner
Associate Editor, Journal of Physiology
Mayo College of Medicine
joyner.michael{at}mayo.edu
Question: Do mechanical mechanisms influence the rapid increase in blood flow following muscle contraction?
Background: Skeletal muscle blood flow is rapidly increased upon muscle contraction. This hyperemic response has recently been attributed to rapid vasodilatation; however, the mechanisms underlying this vasodilatation are unclear. What is clear from empirical analysis is that neural mechanisms, local vasodilators, and nitric oxide and prostaglandins do not influence this rapid vasodilatation
Observations: Using an array of clever manipulations, Kirby et al. tested the hypothesis that mechanical deformation of forearm blood vessels, via acute increases in extravascular pressure, elicits rapid vasodilatation in humans. They found that mechanical influences significantly impact the immediate vasodilatation (first cardiac cycle) observed in response to a brief, single muscle contraction. However, other mechanisms related to muscle contraction sustain the vasodilatation for several more cardiac cycles. They also determined that mechanical influences contribute greatest to moderate-intensity single muscle contractions, with the influence waning as contractions are sustained or repeated.
Significance: This paper makes a key contribution toward understanding the influence of muscular compression on the blood flow in skeletal muscle by demonstrating that mechanically induced vasodilatation is most important in the very initial phase of hyperemia. In fact, this could serve as a feed-forward mechanism that increases muscle blood flow at the onset of exercise. The idea that mechanical mechanisms contribute to exercise hyperemia has come in and out of vogue over many years; the data of Kirby are very clear and suggest this mechanism can be incorporated into models of exercise hyperemia.
Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Kreitzer AC, Malenka RC. Nature 445: 643–647, 2007.[CrossRef][Medline]
Nominated by Julie Kauer
Brown University
julie_kauer{at}brown.edu
Question: What physiological properties differentiate the main efferent targets of the striatum?
Background: Within the basal ganglia, the main efferent targets of the striatum include a direct pathway to the substantia nigra pars reticulate and an indirect pathway to the lateral globus pallidus. The motor deficits observed in Parkinson’s disease (PD) result from an imbalance between the activities of these striatal projection neurons. However, the cellular and synaptic properties that differentiate these circuits are relatively unknown.
Observations: Kreitzer and Malenka determined that, unlike the direct-pathway synapses, the indirect-pathway synapses exhibited a higher probability of releasing neurotransmitter and larger NMDA receptor currents despite similar membrane properties. In addition, they found that the medium spiny neurons of the indirect pathway, but not the direct pathway, express endocannabinoid-mediated long-term depression (eCB-LTD), which is dependent on dopamine D2 receptors. Finally, using models of Parkinson’s disease, they determined that the eCB-LTD associated with the indirect-pathway is absent but can be rescued by D2 receptor agonist or inhibitors of endocannabinoid degradation. In fact, when both a D2 receptor agonist and an inhibitor of endocannabinoid degradation were administered in vivo, they reduced Parkinsonian motor deficits.
Significance: Perhaps the most significant finding of these studies is that endocannabinoid-mediated LTD of indirect-pathway synapses is important for the expression of motor impairments associated with Parkinson’s disease. These findings have obvious implications for understanding motor deficits involving basal ganglia pathway imbalances, but they also suggest that enhancing cannabinoid as well as dopamine levels at indirect pathway synapses might be a valid therapeutic target for the treatment of movement disorders arising from basal ganglia malfunction.
How synaptotagmin promotes membrane fusion.
Martens S, Kozlov MM, McMahon HT. Science 316: 1205–1208, 2007.
Nominated by Julie Kauer
Brown University
julie_kauer{at}brown.edu
Question: How does synaptotagmin-1 (syt1) promote membrane fusion?
Background: Ca2+-induced neurotransmitter release is mediated through an interaction between three soluble NSF attachment protein receptors (SNAREs) and syt1. Syt1, which is associated with the vesicles, has two cytoplamsic C2 domains that each bind Ca2+, thus allowing the vesicles to interact with the presynaptic plasma membrane. This activity is implicated in the triggering of membrane fusion, which is now believed to occur via a hemifusion intermediate. The activation energy of hemifusion is very high and is thought to be related to the curvature deformations generated within the membranes during membrane merging.
Observations: McMahon and colleagues sought to determine whether syt1 promoted membrane fusion by affecting local membrane curvature. They found that upon Ca2+ binding, syt1 promoted SNARE-mediated fusion by lowering the activation barrier via induction of high positive curvature in target membranes. A model is proposed in which the two Ca2+ binding domains of syt1 penetrate the plasma membrane, which results in positive membrane curvature under the SNARE complex ring. This induces buckling of the plasma membrane toward the synaptic vesicle, thus reducing the distance between the two membranes and reducing the energy barrier the membrane has to overcome.
Significance: This interesting paper suggests that syt1 facilitates membrane fusion by calcium-induced membrane deformation. Although further experiments are necessary to determine whether the proposed model is correct, it will be interesting to see whether the local induction of membrane curvature stress by other multiple C2 domain (MC2D)-containing proteins promotes membrane fusion, since MD2C-containing proteins constitute a large protein superfamiliy.
Generation of functional cardiomyocytes from adult mouse spermatogonial stem cells.
Guan K, Wagner S, Unsold B, Maier LS, Kaiser D, Hemmerlein B, Nayernia K, Engel W, Hasenfuss G. Circ Res 100: 1615–1625, 2007.
Nominated by Litsa Kranias
University of Cincinnati
litsa.kranias{at}uc.edu
Question: Can spermatogonial stem cells be differentiated into functional cardiomyocytes?
Background: Embryonic stem cells (ESCs) are derived from the inner cell mass (blastocyst) of an early stage embryo. ESCs are pluripotent, which means they are able to differentiate into all derivatives of the three primary germ layers. In contrast, multipotent progenitor cells found in the adult can only form a limited number of cell types. Recently, however, multipotent adult germline stem cells (maGSCs) from mouse testis have been shown to differentiate into cells from all three germ layers. Thus the feasibility of using these maGSCs to differentiate into cardiomyocytes was explored.
Observations: Guan et al. found that maGSC-derived cardiomyocytes expressed cardiac-specific L-type Ca2+ channels, responded to drugs that modulate Ca2+ channels, and had functional gap junctions. Further analysis established the presence of pacemaker-, ventricle-, atrial-, and Purkinje-like cardiomyocytes. The maGSC-derived cardiomyocytes also exhibited complex functional properties, including a positive or negative response to ß-adrenergic stimulation or Ca2+ blockers and an intact Ca2+ cycling. Finally, when transplanted into normal hearts of mice, maGSCs were able to proliferate and differentiate without tumor formation.
Significance: This work demonstrates that functional cardiomyocytes can be derived from maGSCs. This sets the groundwork for future studies to examine the potential of using these maGSCs in vivo to treat cardiac malfunctions. This is particularly intriguing since this could lead to a new option for the regeneration of human cardiac tissue, without the immunological problems and ethical dilemma associated with the use of ESCs.
Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly, by reducing oxidative stress.
Townsend PA, Davidson SM, Clarke SJ, Khaliulin I, Carroll CJ, Scarabelli TM, Knight RA, Stephanou A, Latchman DS, Halestrap AP. Am J Physiol Heart Circ Physiol (May 4, 2007); 10.1152/ajpheart.01135.2006.
Nominated by Alberto Nasjletti
Editor, American Journal of Physiology—Heart & Circulatory Physiology
New York Medical College
alberto_nasjletti{at}nymc.edu
Question: Does urocortin prevent heart damage directly via the translocation of PKC
or indirectly by reducing oxidative stress?
Background: Urocortin is a peptide that is closely related to corticotrophin-releasing factor (CRF). In fact, urocortin binds to the two CRF G-protein-coupled receptors, CRF-R1 and CRF-R2; however, only CRF-R2 is expressed in the heart. Urocortin functions to protect the heart from ischemia/reperfusion damage, and available evidence suggest that this is accomplished by preventing the opening of mitochondrial permeability transition pores (MPTPs). Some argue that inhibition of MPTPs is mediated directly by phosphorylation, whereas others suggest that inhibition is secondary to a reduction in oxidative stress and Ca2+ overload.
Observations: In this report, Townsend et al. provide the first evidence that urocortin can inhibit MPTP opening in the intact heart. Next, they sought to understand the mechanism(s) that underlie this phenomenon. They determined that urocortin protects hearts from reperfusion injury by indirectly inhibiting MPTP opening via reduced oxidative stress and/or Ca2+ overload and not directly through translocation of PKC to the mitochondria.
Significance: These data suggest that urocortin protects the heart indirectly by inhibiting MPTPs; however, this mechanism appears to involve a PKC-mediated reduction in oxidative stress. Understanding the mechanism by which urocortin protects the heart has therapeutic significance. It is conceivable that agents like urocortin can be administered during cardiac surgery to minimize the effects of ischemic damage.
Abnormal hair development and apparent follicular transformation to mammary gland in the absence of hedgehog signaling. Gritli-Linde A, Hallberg K, Harfe BD, Reyahi A, Kannius-Janson M, Nilsson J, Cobourne MT, Sharpe PT, McMahon AP, Linde A. Dev Cell 12: 99–112, 2007.[CrossRef][Web of Science][Medline]
Nominated by Robert Weinberg
Massachusetts Institute of Technology
weinberg{at}wi.mit.edu
Question: What role does hedgehog signaling have in hair development?
Background: Hair follicle (HF) formation is controlled by numerous molecules, including a signaling system known as the "hedgehog pathway," which also controls the development of certain organs. In the skin, the hedgehog system signals stem cells to differentiate into certain types of cells. Smoothened (Smo), an obligatory molecular component of hedgehog signaling, was ablated to study the role of hedgehog signaling in HF formation.
Observations: Under normal physiological conditions, the stem cells at the hair follicles lie in niches. In the transgenic mice that Gritli-Linde et al. created, the niches that protect the stem cells are missing. This disruption of the niche allows the stem cells to initiate hair formation at inappropriate times. Interestingly, instead of the stem cells developing into hair, they develop into mammary gland cells.
Significance: These novel findings suggest that the hedgehog pathway has several functions associated with the integrity and identity of the developing HF, which is likely to be of interest to many scientists. First, if the signaling system that regulates the behavior of these stem cells is elucidated, there may be a new treatment for hair loss. Moreover, intensive hedgehog signaling has been associated with cancer; thus these results perhaps may lead to new treatment options for cancer. Finally, development of hair from the follicles occurs in a similar manner to the way teeth develop in tooth buds; thus studying the mechanisms by which hair develops is also of interest to odontologists.
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