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Papers by robert barchi

PubMed, May 1, 1991

Approximately one third of the Na+ channels expressed in denervated or developing skeletal muscle... more Approximately one third of the Na+ channels expressed in denervated or developing skeletal muscle are tetrodotoxin (TTX) insensitive, with a Kd for channel blockade of approximately 1 microM, similar to that found for cardiac Na+ channels. We have recently reported the cloning of a putative Na+ channel subtype that is characteristic of denervated and developing skeletal muscle (SkM2), the deduced amino acid sequence of which is identical to that of a Na+ channel cDNA isolated from heart. We have now examined the functional properties of SkM2 Na+ channels after expression in Xenopus oocytes. We found that the efficiency of expression of constructs containing the SkM2 clone was strongly dependent on the amount of 5'-untranslated region (5'UTR) included. Constructs containing a 206-nucleotide 5'UTR were expressed poorly, whereas constructs from which most of the 5'UTR was removed were expressed well. The channels showed rapid voltage-dependent activation and inactivation. In addition, SkM2 Na+ channels were insensitive to low concentrations of TTX but were ultimately blocked by this toxin, with a Kd of 1.9 microM. The TTX block exhibited use dependence. Finally, SkM2 Na+ channels were not blocked by 100 nM mu-conotoxin, which blocks Na+ channels in innervated skeletal muscle in the low nanomolar concentration range. These data indicate that SkM2 Na+ channels are the TTX-insensitive Na+ channels found in denervated or developing skeletal muscle and are identical to the TTX-insensitive Na+ channels from heart.

Proceedings of the National Academy of Sciences of the United States of America, Oct 1, 1984

The Journal of Neuroscience, Sep 1, 1984

Proceedings of the National Academy of Sciences of the United States of America, Dec 20, 1994

Proceedings of the National Academy of Sciences of the United States of America, Jan 15, 1992

Archives of Neurology, 1997

In striving to improve the quality of patient care, today's academic neurology department... more In striving to improve the quality of patient care, today's academic neurology department faces special problems. Factors that are inherent in the department's broader academic mission and in the organization of a major teaching hospital can compromise practice efficiency, reduce ease of access, and undermine cost competitiveness. However, the same environment also provides the opportunity to exploit areas of unique clinical expertise, create value-added services, and develop regional approaches to service-line integration and disease management strategies. A major challenge for the academic department is to validate the quality and efficiency of its current services while assuming a leadership role in the development of new approaches to quality improvement. This challenge must be met without losing sight of the department's equally important parallel commitments to research and education.

Neurobiology of Disease, 1999

In rats treated with high-dose corticosteroids, skeletal muscle that is denervated in vivo (stero... more In rats treated with high-dose corticosteroids, skeletal muscle that is denervated in vivo (steroiddenervated) develops electrical inexcitability similar to that seen in patients with acute quadriplegic myopathy. To determine whether changes in muscle gene transcription might underlie inexcitability of steroid-denervated muscle we performed RNase protection assays to quantitate adult (SkM1) and embryonic (SkM2) sodium channel isoforms and chloride channel (CLC-1) mRNA levels in control, denervated, steroid-innervated, and steroid-denervated skeletal muscle. While SkM1 mRNA levels were relatively unaffected by denervation or steroid treatment, SkM2 mRNA levels were increased by both. These effects were synergistic and high levels of SkM2 mRNA were expressed in denervated muscle exposed to corticosteroids. Skeletal muscle CLC-1 mRNA levels were decreased by denervation. To better understand the marked upregulation of SkM2 in steroid-denervated muscle we examined changes in myogenin and glucocorticoid receptor mRNA levels. However, changes in these mRNA levels cannot account for the upregulation of SkM2 in steroid-denervated muscle. 1999 Academic Press

S-1 My year as chair of the Faculty Senate has been a most fascinating, challenging, and rewardin... more S-1 My year as chair of the Faculty Senate has been a most fascinating, challenging, and rewarding one. Vivian Seltzer, past chair, and Peter Conn, chair-elect, and I have benefited immensely from the insights of our colleagues on the Senate Executive Committee and the various Senate committees. We have enjoyed a cordial working relationship with President Rodin, Michael Wachter, Interim Provost for the first half of the year, and Robert Barchi, who took office as Provost in February. The President and the Provost met with us on a regular basis and also appeared on several occasions to discuss important matters with the Senate Executive Committee and to respond to questions from SEC members. We look forward to continued close collaboration during 1999-2000. The three chairs met periodically with John Fry, Executive Vice President, to discuss urgent matters that fell within his scope of responsibility. We found him remarkably forthcoming and well-informed about a wide range of activi...

Society of General Physiologists series, 1987

Sodium channel proteins have now been isolated from a number of nerve and muscle preparations. Al... more Sodium channel proteins have now been isolated from a number of nerve and muscle preparations. All are characterized by the presence of a very large glycoprotein subunit of approximately 260 kilodaltons which may contain the structural features required for voltage-dependent channel gating and cation selectivity. These purified proteins have been reconstituted into vesicle systems and planar bilayers and demonstrate the ensemble and single-channel behavior characteristic of the native sodium channel. Although the sodium channel from eel appears to consist of only the 260-kilodalton protein, the channels from rat brain and rat or rabbit skeletal muscle contain one or more smaller subunits of 37-39 kilodaltons. In skeletal muscle, a 38-kilodalton subunit is present in both conventionally purified channel and channel isolated with immunoaffinity techniques. The stoichiometry of the large (alpha) and the small (beta) subunits appears to be 1:1 in skeletal muscle but 1:2 in rat brain. Th...

Electroencephalography and clinical neurophysiology. Supplement, 1978

The myotonic syndrome of delayed relaxation in striated muscle associated with repetitive membran... more The myotonic syndrome of delayed relaxation in striated muscle associated with repetitive membrane electrical activity is characteristic of a number of hereditary disorders in animals and man. This state of pathologic membrane hyperexcitability is also seen as a consequence of intoxication with several classes of chemicals. In most of these states an increase in muscle membrane resistance due to a specific reduction in sarcolemmal GCl can be demonstrated. Computer simulations have indicated that such a reduction in GCl alone could account for the observed repetitive electrical activity. Controlled reduction of GCl in normal muscle, using aromatic monocarboxylic acids, produces a myotonic syndrome. This myotonia resembles that seen in hereditary disease in its contractile characteristics, its intracellular electrical behavior and its response to diphenylhydantoin and procainamide. The effects of variations in temperature and divalent cation concentration seen in this system parallel ...

Journal of Neurochemistry, 1990

The Journal of General Physiology, 1998

The D4/S4-5 interhelical region plays a role in sodium channel fast inactivation. Examination of ... more The D4/S4-5 interhelical region plays a role in sodium channel fast inactivation. Examination of S4-5 primary structure in all domains suggests a possible amphipathic helical conformation in which a conserved group of small hydrophobic residues occupies one contiguous surface with a more variable complement of nonpolar and polar residues on the opposite face. We evaluated this potential structure by replacing each residue in D4/S4-5 of the rat SkM1 skeletal muscle sodium channel with substitutions having different side chain properties. Of the 63 mutations analyzed, 44 produced functional channels. P1473 was intolerant of substitutions. Nonpolar substitutions in the conserved hydrophobic region were functionally similar to wild type, while charged mutations in this region before P1473 were nonfunctional. Charged mutations at F1466, M1469, M1470, and A1474, located on the opposite surface of the predicted helix, produced functional channels with pronounced slowing of inactivation, sh...

Brain Research, 1972

ABSTRACT The activity of 2′, 3′-cyclic nucleotide 3′-phosphodiesterase in the sciatic nerve of ra... more ABSTRACT The activity of 2′, 3′-cyclic nucleotide 3′-phosphodiesterase in the sciatic nerve of rats was determined during the myelination phase of postnatal development. In contrast to the large increase in activity of this enzyme in myelinating cerebrum and cerebellum, the specific activity of the diesterase in sciatic nerve remains constant. It seems unlikely, therefore, that this diesterase is a component of the myelin sheath in sciatic nerve.Determinations of cyclic nucleotide diesterase activity in demyelinated tissue (plaques) of multiple sclerosis patients showed that the enzyme is nearly completely absent from this tissue. These data confirm and support the view that the diesterase is a component of myelin in the CNS.The diesterase was demonstrated in polyacrylamide gels containing the electrophoretically separated rat CNS myelin proteins by staining for enzymatic activity. The enzyme is tentatively identified as a high molecular weight minor protein component of myelin; it does not correspond in its electrophoretic behavior to either the basic (encephalitogenic) protein or the proteolipid protein of myelin.

Archives of Neurology, 1975

The muscle membrane in myotonia congenita is characterized by a normal resting potential with a g... more The muscle membrane in myotonia congenita is characterized by a normal resting potential with a greatly increased resting resistance usually attributed to a decrease in membrane chloride permeability (PC1). In this report, the hypothesis that decreased PC1 alone can account for the repetitive action potentials of myotonia is tested with a mathematical model of the muscle membrane and is shown to be valid. Reduction of Pc1 to 20% of control values will produce myotonic activity in response to a single stimulus. Membrane resistance and potential approximate those found experimentally. The model predicts that increasing external K+ will aggravate myotonia due to a reduction of PC15 while decreasing Kout will prevent repetitive spiking. Further, myotonia can be prevented by reducing peak membrane sodium permeability or by shifting the voltage dependency of the membrane rate constants for sodium in a depolarizing direction. These results are shown to correlate well with clinical observtonia.

Annals of Neurology, 1996

and the Working Groups of the Long Range Planning Committee By most measures, academic neurology ... more and the Working Groups of the Long Range Planning Committee By most measures, academic neurology is thriving as never before, yet convening forces are changing the face of academic neurology. This report focuses on changes that academic neurology and the American Neurological Association could undertake to seize new opportunities and resist damaging potential changes. These proposals can be categorized in the following four major goals: (1) enhance the quality of a smaller neurology workforce and augment the recruitment of gifted young neuroscientists into neurology; (2) foster new diversity in neurological investigation, including clinical research in neurology; (3) document the benefits and relative costs of neurological care, in general, and of academic neurology, in particular; and (4) foster the role of neurologists as teachers to medical caregivers at all levels, including medical students, nonneurological house staff, and primary practitioners.

Journal of Biological Chemistry, 1998

We have characterized a group of cis-regulatory elements that control muscle-specific expression ... more We have characterized a group of cis-regulatory elements that control muscle-specific expression of the rat skeletal muscle type 1 sodium channel (SkM1) gene. These elements are located within a 3.1-kilobase fragment that encompasses the 5-flanking region, first exon, and part of the first intron of SkM1. We sequenced the region between ؊1062 and ؉311 and determined the start sites of transcription; multiple sites were identified between ؉1 and ؉30. The basal promoter (؊65/؉11) lacks cell-type specificity, while an upstream repressor (؊174/؊65) confers muscle-specific expression. A positive element (؉49/؉254) increases muscle-specific expression. Within these broad elements, two E boxes play a pivotal role. One E box at ؊31/؊26 within the promoter, acting in part through its ability to bind the myogenic basic helix-loop-helix proteins, recruits additional factor(s) that bind elsewhere within the SkM1 sequence to control positive expression of the gene. A second E box at ؊90/؊85 within the repressor controls negative regulation of the gene and acts through a different complex of proteins. Several of these cis-regulatory elements share both sequence and functional similarities with cis-regulatory elements of the acetylcholine receptor ␦-subunit; the different arrangement of these elements may contribute to unique expression patterns for the two genes.