Educational Forum with Clinical Studies Current Science and Research

December 29, 2010

Excitation-contraction coupling from the 1950s into the new millennium. Xanya Sofra Weiss Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 11:12 pm

Dulhunty AF.

1. Excitation-contraction coupling is broadly defined as the process linking the action potential to contraction in striated muscle or, more narrowly, as the process coupling surface membrane depolarization to Ca(2+) release from the sarcoplasmic reticulum. 2. We now know that excitation-contraction coupling depends on a macromolecular protein complex or ‘calcium release unit’. The complex extends the extracellular space within the transverse tubule invaginations of the surface membrane, across the transverse tubule membrane into the cytoplasm and then across the sarcoplasmic reticulum membrane and into the lumen of the sarcoplasmic reticulum. 3. The central element of the macromolecular complex is the ryanodine receptor calcium release channel in the sarcoplasmic reticulum membrane. The ryanodine receptor has recruited a surface membrane L-type calcium channel as a ‘voltage sensor’ to detect the action potential and the calcium-binding protein calsequestrin to detect in the environment within the sarcoplasmic reticulum. Consequently, the calcium release channel is able to respond to surface depolarization in a manner that depends on the Ca(2+) load within the calcium store. 4. The molecular components of the ‘calcium release unit’ are the same in skeletal and cardiac muscle. However, the mechanism of excitation-contraction coupling is different. The signal from the voltage sensor to ryanodine receptor is chemical in the heart, depending on an influx of external Ca(2+) through the surface calcium channel. In contrast, conformational coupling links the voltage sensor and the ryanodine receptor in skeletal muscle. 5. Our current understanding of this amazingly efficient molecular signal transduction machine has evolved over the past 50 years. None of the proteins had been identified in the 1950s; indeed, there was debate about whether the molecules involved were, in fact, protein. Nevertheless, a multitude of questions about the molecular interactions and structures of the proteins and their interaction sites remain to be answered and provide a challenge for the next 50 years.

Xanya Sofra Weiss

Xanya Sofra Weiss

Control of calcium in skeletal muscle excitation-contraction coupling: implications for malignant hyperthermia. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 11:04 pm

Wingertzahn MA, Ochs RS.

The missing link in our understanding of excitation-contraction coupling (ECC) in skeletal muscle is the mechanism by which Ca2+ increases in the cytosol to trigger contraction. We discuss here a general background of intracellular Ca2+ handling, some characteristics of the major proteins involved in Ca2+ flow during ECC, and mechanisms currently believed to explain the increase in Ca2+ upon stimulation of muscle cells. These mechanisms include the calcium-induced calcium release, the direct coupled mechanism in which a plasma membrane and sarcoplasmic reticulum membrane protein interact, and mechanisms involving Ca2+ secretagogues that are known to elicit increases in calcium in other cells, inositol trisphosphate, and cyclic ADP ribose. We also consider possible roles for proteins associated with the principal calcium release channel of the sarcoplasmic reticulum, the ryanodine receptor. Finally, we discuss malignant hyperthermia, a disease associated directly with aberrant control of muscle cell calcium release. Copyright 1998 Academic Press.

Xanya Sofra Weiss

Xanya Sofra Weiss

Characterization of Voltage-Gated Potassium Channels in Human Neural Progenitor Cells. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 12:19 am
Grit Schaarschmidt, Florian Wegner, Sigrid C. Schwarz, Hartmut Schmidt, Johannes Schwarz,
Background: Voltage-gated potassium (Kv) channels are among the earliest ion channels to appear during brain development, suggesting a functional requirement for progenitor cell proliferation and/or differentiation. We tested this hypothesis, using human neural progenitor cells (hNPCs) as a model system.
Methodology/Principal Findings: In proliferating hNPCs a broad spectrum of Kv channel subtypes was identified using quantitative real-time PCR with a predominant expression of the A-type channel Kv4.2. In whole-cell patch-clamp recordings Kv currents were separated into a large transient component characteristic for fast-inactivating A-type potassium channels (IA) and a small, sustained component produced by delayed-rectifying channels (IK). During differentiation the expression of IA as well as A-type channel transcripts dramatically decreased, while IK producing delayed-rectifiers were upregulated. Both Kv currents were differentially inhibited by selective neurotoxins like phrixotoxin-1 and a-dendrotoxin as well as by antagonists like 4-aminopyridine, ammoniumchloride, tetraethylammonium chloride and quinidine. In viability and proliferation assays chronic inhibition of the A-type currents severely disturbed the cell cycle and precluded proper hNPC proliferation, while the blockade of delayed-rectifiers by a-dendrotoxin increased proliferation.
Conclusions/Significance: These findings suggest that A-type potassium currents are essential for proper proliferation of immature multipotent hNPCs.
Xanya Sofra Weiss

Transport Mechanisms in Iontophoresis. II. Electroosmotic Flow and Transference Number Measurements for Hairless Mouse Skin. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 12:08 am

Abstract Previous studies suggest that bulk fluid flow by electroosmosis is a significant factor in iontophoresis and may provide an explanation for the observed enhanced transport of neutral species. In a charged membrane, the solution carries a net charge and thus experiences a volume force in an electric field, which causes volume flow (J v in the direction of counterion flow. J vdata were obtained for hairless mouse skin (HM) as a function of pH, concentration of NaCl, current density, and time. Volume flow was measured by timing fluid movement in horizontal capillary tubes attached to the anode and cathode (Ag/AgCl) compartments. By convention, the sign of J v is taken as positive when the volume flow is in the same direction as positive current flow. Experimental mean values were in the range 0 to + 37 µl/cm2 hr, depending on the experimental conditions. Volume flow of this magnitude is large enough to have significant impact on flow of both ions and neutral species. The positive sign for J vindicates that HMS is negative in the pH range studied (3.8–8.3). J vdecrease with time, decrease with increasing NaCl concentration, are much lower at pH 3.8 than at the higher pH’s, and increase with current density. Effective transference numbers, determined from membrane potential measurements, showed significant pH dependence, consistent with a small negative charge on the membrane at mid pH’s and charge reversal around pH 4. Both electrical resistance and J v data indicate changes in transport properties occur when HMS is subjected to an electric field.

Xanya Sofra Weiss

Xanya Sofra Weiss

Ion Channels: Febrile convulsions, ataxia, developmental delay, and obesity: a new syndrome? Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 12:02 am

Febrile convulsions, ataxia, developmental delay, and obesity: a new syndrome?

D LevN WatembergA AviramJ FishoffE AntmanT Lerman-Sagie

We describe the association of recurrent complicated febrile convulsions, developmental delay, ataxia, and obesity in three unrelated girls. The three girls, aged 3 to 4 years, were all born to healthy, nonconsanguineous parents and have normal siblings. Their birth weight was appropriate for gestational age. They are not dysmorphic and have normal head circumference. Development is delayed; they all walked with an ataxic gait after the age of 2 years and started speaking at 3 years. Their growth charts are remarkably alike: they initially had a normal growth curve and around 24 months of age started to gain weight excessively. They all continue to suffer from complicated febrile seizures, which started before 12 months of age, and are resistant to prophylactic anticonvulsants. Metabolic evaluation is normal. They have normal magnetic resonance images and electroencephalograms. Fragile X and Prader-Willi syndromes were ruled out. We suggest that this is a new mental retardation syndrome that should be considered in children with recurrent febrile convulsions, developmental delay, and obesity. In a recent study, mutations in the beta4 calcium channel were identified in the mutant epileptic mouse that presents with epilepsy, mental retardation, and ataxia. We hypothesize that a calcium channel gene may be involved in this syndrome.

Xanya Sofra Weiss

Xanya Sofra Weiss

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