PubMed · 13816591
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J W DICKERSON, E M WIDDOWSON. 1960. Chemical changes in skeletal muscle during development.. https://doi.org/10.1042/bj0740247
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1. In muscle, intracellular calcium concentration, hence skeletal muscle force and cardiac output, is regulated by uptake and release of calcium from the sarcoplasmic reticulum (SR). The ryanodine receptor (RyR) forms the calcium release channel in the SR. 2. Calcium release through RyRs is modulated by a wide variety of endogenous molecules, including small diffusible ligands such as ATP, Ca2+ and Mg2+. The regulation of RyR channels by ATP, Ca2+ and Mg2+ is a complex interplay of several regulatory mechanisms, which are still being unravelled. Consequently, it is not clearly known how RyRs are regulated in resting muscle and during contraction. 3. The present paper reviews factors controlling the activity of RyRs in skeletal and cardiac muscle with an emphasis on mechanistic insights derived from single channel recording methods. 4. In addition, the nature of dihydropyridine receptor (DHPR) control of RyRs in skeletal muscle derived from experiments with peptide fragments of the DHPR II-III loop is reviewed. 5. Finally, recent experiments on coupled RyRs in lipid bilayers and their potential for resolving the elusive mechanisms controlling calcium release during cardiac contraction are discussed.
Eu et al., reported that O2 dynamically controls the redox state of 6-8 out of 50 thiols per skeletal ryanodine receptor (RyR1) subunit and thereby tunes the response of Ca2+-release channels to authentic nitric oxide (NO) [J.P. Eu, J. Sun, L. Xu, J.S. Stamler, G. Meissner, The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions, Cell 102 (2000) 499-509]. A role for O2 was based on the observation that RyR1 can be activated by submicromolar NO at physiological ( approximately 10 mmHg) but not ambient (approximately 150 mmHg) pO2. At ambient pO2, these critical thiols were oxidized but incubation at low pO2 reset the redox state of these thiols, closed RyR1 channels and made these thiols available for nitrosation by low NO concentrations. Eu et al., postulated the existence of a redox/O2sensor that couples channel activity to NO and pO2 and explained that "the nature of the 'redox/O2 sensor' that couples channel activity to intracellular redox chemistry is a mystery". Here, we re-examined the effect of pO2 on RyR1 and find that incubation of RyR1 at low pO2 did not alter channel activity and NO (0.5-50 microM) failed to activate RyR1 despite a wide range of pO2 pre-incubation conditions. We show that low levels of NO do not activate RyR1, do not reverse the inhibition of RyR1 by calmodulin (CaM) even at physiological pO2. Similarly, the pre-incubation of SR vesicles in low pO2 (for 10-80 min) did not inhibit channel activity or sensitization of RyR1 to NO. We discuss the significance of these findings and propose that caution should be taken when considering a role for pO2 and nitrosation by NO as mechanisms that tune RyRs in striated muscles.
Although still in a developmental stage, naked DNA vaccines are already the most important advancement in the history of vaccinology. Both the injection of plasmid DNA in experimental animals by different routes and preclinical studies, demonstrate the induction of protective immunity against different pathogens. Therapeutic application of DNA vaccines are well under way. In spite of the growing understanding about methods and routes of immunisation, both the early mechanisms by which DNA dependent immunisation occurs as well as the transfected cell types remain poorly understood. There is abundant experimental evidence that myocytes, keratinocytes and dendritic cells play an important role in the induction of the immune response. There is also an ongoing controversy on the relative importance of each one of these cell types. The aim of this paper is to review the current state of affairs regarding the understanding of the cell types participating in an immune response to the injection of a plasmid DNA vaccine. It is probably unlikely that only one and the same cell type would be the transfected cell and the one presenting the immunising peptide on MHC class II and I. An important step towards the understanding of DNA immunising mechanisms would be to elucidate plasmid DNA transfection. Is there a cell type that has specific receptors capturing the plasmid, expressing it and transferring its products to the antigen-presenting cell?