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Sodium Channel Expression
Published by Anonymous on 2007/9/27 (1477 reads)
1: Clin Endocrinol (Oxf). 2005 May;62(5):547-53.


Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism.

Edelheit O, Hanukoglu I, Gizewska M, Kandemir N, Tenenbaum-Rakover Y, Yurdakök M, Zajaczek S, Hanukoglu A.

Department of Molecular Biology, College of Judea and Samaria, Ariel, Israel.

OBJECTIVES: Multisystem pseudohypoaldosteronism (PHA) is a rare autosomal recessive aldosterone unresponsiveness syndrome that results from mutations in the genes encoding epithelial sodium channel (ENaC) subunits alpha, beta and gamma. In this study we examined three PHA patients to identify mutations responsible for PHA with different clinical presentations. PATIENTS: All three patients presented uniformly with symptoms of severe salt-loss during the first week of life and were hospitalized for up to a year. Beyond infancy, one of the patients showed mild renal salt loss and had no lower respiratory tract infections until 8 years of age, while the other patients continue with a severe course. RESULTS: We sequenced the complete coding regions and intron-exon junctions of the genes encoding alpha, beta and gamma subunits of ENaC for all patients. The results revealed that the mild case represents a novel compound heterozygote including a missense (Gly327Cys) mutation in the alphaENaC gene. Sequences of relatives over three generations confirmed that the missense mutation co-segregates with PHA. This mutation was not found in 60 control subjects. The other patients with severe PHA had two homozygous mutations, a novel deletion mutation in exon 8 of the alphaENaC gene and a splice site mutation in intron 12 of the betaENaC gene. Most of the PHA-causing mutations appear in the alphaENaC gene located on chromosome 12 rather than in the beta and gammaENaC genes located tandemly on chromosome 16. However, the frequency of sequence variants in patients and control subjects showed no difference between genes. CONCLUSIONS: Severe PHA cases are associated with mutations leading to absence of normal-length alpha, beta or gammaENaC, while a mild case has been found to be associated with a missense mutation in alphaENaC. The predominance of PHA-causing mutations in the alphaENaC gene may be related to the function of this subunit.

Publication Types:
Case Reports
Research Support, Non-U.S. Gov't
Review

PMID: 15853823 [PubMed - indexed for MEDLINE]

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2: Ann N Y Acad Sci. 2002 Oct;971:127-34.


Regulation of voltage-dependent sodium channel expression in adrenal chromaffin cells: involvement of multiple calcium signaling pathways.

Kobayashi H, Shiraishi S, Yanagita T, Yokoo H, Yamamoto R, Minami S, Saitoh T, Wada A.

Department of Pharmacology, Miyazaki Medical College, Miyazaki 889-1692, Japan. hkobayas@post.miyazaki-med.ac.jp

The density and electrical activity of cell surface voltage-dependent Na(+) channels are key determinants regulating the neuronal plasticity including development, differentiation, and regeneration. Abnormalities of Na(+) channels are associated with various neurological diseases. In this paper, we review the regulatory mechanisms of cell surface Na(+) channel expression mediated by Ca(2+) signaling pathways in cultured bovine adrenal chromaffin cells. Sustained, but not transient, elevation of intracellular Ca(2+) concentration reduced the number of cell surface Na(+) channels. The reduction of Na(+) channels was suppressed by an inhibitor of calpain, a Ca(2+)-dependent protease, and by an inhibitor of protein kinase C (PKC). The activation of conventional PKC-alpha and novel PKC-epsilon reduced cell surface Na(+) channels by the acceleration of internalization of the channels and by the increased degradation of Na(+) channel alpha-subunit mRNA, respectively. On the contrary, the activation of PKC-epsilon increased Na(+) channel beta(1)-subunit mRNA level. The inhibition of calcineurin, a Ca(2+)/calmodulin-dependent protein phosphatase 2B, by immunosuppressants upregulated cell surface Na(+) channels by both stimulating externalization and inhibiting internalization of the channels without changing Na(+) channel alpha- and beta(1)-subunit mRNA levels. Thus, the signal transduction pathways mediated by intracellular Ca(2+) modulate cell surface Na(+) channel expression via multiple Ca(2+)-dependent events, and the changes in the intracellular vesicular trafficking are the important mechanisms in the regulation of Na(+) channel expression.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 12438102 [PubMed - indexed for MEDLINE]

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3: Novartis Found Symp. 2002;241:109-20; discussion 120-3, 226-32.


Sodium channel gene expression and epilepsy.

Noebels JL.

Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.

Na+ channelopathies that prolong membrane depolarization lead to neuronal bursting, abnormal network synchronization, and various patterns of episodic neurological disorders, including epilepsy. Two distinct pathways exist for generating epileptic phenotypes based on inherited disorders of voltage-gated Na+ ion channels. The first pathway is direct, involving mutations in genes encoding the pore-forming alpha1 and regulatory beta subunits of the channel that directly alter current amplitude or kinetics. These mutations favour repetitive firing and network hyperexcitability, although often the circuits most vulnerable to functional alterations are not easy to identify and the emergent clinical phenotypes are difficult to predict. The second pathway involves mutation of other genes that lead to downstream modifications in Na+ channel expression. Two clinically relevant examples of localization-related vulnerability in brain are described that illustrate how specific phenotypes arise from both direct and secondary pathways. Selective expression of the cardiac SCN5A channel within limbic regions of brain may explain why mutation of the gene for this tetrodotoxin-insensitive current may be associated with seizures. Ectopic expression of type II Na+ channels along axonal internodes in hypomyelinated brain may reveal why deletion of the myelin basic protein gene leads to subcortical seizure patterns. Analysis of these models offers insight into developmental processes that control the cellular expression and plasticity of Na+ channel genes, and will help to clarify mechanisms of hereditary Na+ channel-based epileptogenesis.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 11771641 [PubMed - indexed for MEDLINE]

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4: Philos Trans R Soc Lond B Biol Sci. 2000 Feb 29;355(1394):199-213.


The neuron as a dynamic electrogenic machine: modulation of sodium-channel expression as a basis for functional plasticity in neurons.

Waxman SG.

Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA. stephen.waxman@yale.edu

Neurons signal each other via regenerative electrical impulses (action potentials) and thus can be thought of as electrogenic machines. Voltage-gated sodium channels produce the depolarizations necessary for action potential activity in most neurons and, in this respect, lie close to the heart of the electrogenic machinery. Although classical neurophysiological doctrine accorded 'the' sodium channel a crucial role in electrogenesis, it is now clear that nearly a dozen genes encode distinct sodium channels with different molecular structures and functional properties, and the majority of these channels are expressed within the mammalian nervous system. The transcription of these sodium-channel genes, and the deployment of the channels that they encode, can change significantly within neurons following various injuries. Moreover, the transcription of these genes and the deployment of various types of sodium channels within neurons of the normal nervous system can change markedly as neurons respond to changing milieus or physiological inputs. As a result of these changes in sodium-channel expression, the membranes of neurons may be retuned so as to alter their transductive and/or encoding properties. Neurons within the normal and injured nervous system can thus function as dynamic electrogenic machines with electroresponsive properties that change not only in response to pathological insults, but also in response to shifting functional needs.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

PMID: 10724456 [PubMed - indexed for MEDLINE]

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5: Pain. 1999 Aug;Suppl 6:S133-40.


The molecular pathophysiology of pain: abnormal expression of sodium channel genes and its contributions to hyperexcitability of primary sensory neurons.

Waxman SG.

Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA. stephen.waxman@yale.edu

Although hyperexcitability and/or increased baseline sensitivity of primary sensory neurons following nerve injury can lead to abnormal burst activity associated with pain, the molecular mechanisms that contribute to it are not fully understood. Early studies demonstrated that, following axonal injury, neurons can display changes in excitability suggesting increased sodium channel expression. Consistent with this, abnormal accumulations of sodium channels have been observed at the tips of injured axons. But we now know that nearly a dozen distinct sodium channels are encoded by different genes, raising the question, what types of sodium channels underlie hyperexcitability of primary sensory neurons following injury? My laboratory has used molecular, electrophysiological, and pharmacological techniques to answer this question. Our studies have demonstrated that multiple sodium channels, with distinct physiological properties, are expressed within small dorsal root ganglion (DRG) neurons, which include nociceptive cells. Several DRG and trigeminal neuron-specific sodium channels have now been cloned and sequenced. There is a dramatic change in sodium channel expression in DRG neurons, with down-regulation of the SNS/PN3 and NaN sodium channel genes and up-regulation of previously silent Type III sodium channel gene, following injury to the axons of these cells. These changes in sodium channel gene expression can produce electrophysiological changes in DRG neurons which poise them to fire spontaneously or at inappropriate high frequencies. We have also observed changes in sodium channel gene expression in experimental models of inflammatory pain. The dynamic nature of sodium channel gene expression in DRG neurons, and the changes which occur in sodium channel and sodium current expression in these cells following axonal injury and in inflammatory pain models, suggest that abnormal expression of sodium channels contributes to the molecular pathophysiology of pain.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

PMID: 10491982 [PubMed - indexed for MEDLINE]

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6: Kidney Int Suppl. 1998 Sep;67:S109-14.


Epithelial sodium channel regulatory proteins identified by functional expression cloning.

Vallet V, Horisberger JD, Rossier BC.

Institut de Pharmacologie et de Toxicologie, l'Université, Lausanne, Switzerland.

We describe here our current strategy for identifying and cloning proteins involved in the regulation of the epithelial sodium channel (ENaC). We have set up a complementation functional assay in the Xenopus laevis oocyte expression system. Using this assay, we have been able to identify a channel-activating protease (CAP-1) that can increase ENaC activity threefold. We propose a novel extracellular signal transduction pathway controlling ionic channels of the ENaC gene family that include genes involved in mechanotransduction (degenerins), in peptide-gated channels involved in neurotransmission (FaNaCh), in proton-gated channels involved in pH sensing (ASIC) or pain sensation (DRASIC).

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 9736264 [PubMed - indexed for MEDLINE]

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7: Dev Neurosci. 1996;18(3):139-52.


Sodium channel expression: a dynamic process in neurons and non-neuronal cells.

Black JA, Waxman SG.

Department of Neurology, Yale University School of Medicine, New Haven, Conn, USA.

Although voltage-gated sodium channels have been most carefully studied in neurons, these channels are also present in nonexcitable cells within the nervous system and outside the nervous system. The mRNAs and protein for rat brain type sodium channels are expressed in both non-neuronal nervous system cells (glial cells) and in some cell types outside the nervous system. In most of these cell types, the expression of sodium channels is dynamic, with the levels and proportions of various sodium channel subtypes changing during development, and in response to injury and upon exposure to neurotrophins. It is likely that, in the near future, we will understand the roles played by sodium channels in each of these cell types, and the regulatory mechanisms that control expression of these channels.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

PMID: 8894443 [PubMed - indexed for MEDLINE]

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8: Kidney Int. 1995 Oct;48(4):950-5.


Expression cloning of the epithelial sodium channel.

Canessa CM, Horisberger JD, Schild L, Rossier BC.

Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA.

Publication Types:
In Vitro
Review

PMID: 8569104 [PubMed - indexed for MEDLINE]

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9: Adv Neurol. 1993;59:135-55.


Dynamic aspects of sodium channel expression in astrocytes.

Waxman SG, Sontheimer H, Black JA, Minturn JE, Ransom BR.

Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8380514 [PubMed - indexed for MEDLINE]

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10: J Membr Biol. 1992 Feb;125(3):193-205.


Tissue-specific expression of the voltage-sensitive sodium channel.

Mandel G.

Department of Neurobiology and Behavior, State University of New York, Stony Brook 11794.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 1313507 [PubMed - indexed for MEDLINE]
 

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