From Andy Davidson:
Just read your stuff on Goldberg and particularly Olin (shame it’s not in English):
“The hypothesis relates to and enlarges the theory/hypothesis that the Swedish research group RÃ¶nnbÃ¤ck-Hansson formulated regarding defects/damage in the astrogliacell membrane caused by disturbances in the transport through the membrane of e.g. the important energy- and signal substance glutamate.”
You know how I go on about the significance of studies showing EMR effects on nitric oxide synthase; well this seems to tie in pretty well with the RÃ¶nnbÃ¤ck-Hansson theory.
eg, from http://www.whatislife.com/reader2/Metabolism/pathway/no.html:
The activity of eNOS and nNOS is controlled by tetrahydrobiopterin and Ca/CaM availability because these two cofactors are needed for the proper dimer formation of an active synthetase. The dependence on calmodulin has been used as a model to explain the role of glutamate in neurotoxicity in the central nervous system. Neurotoxicity is a mechanism of glutamate induced neuronal cell death. The immediate effect of glutamate on neurons is its role in activating glutamate receptor, namely to pharmacological subtypes known as NMDA Receptors (NMDA is a methylated derivative of aspartate). Glutamate receptors are selective for calcium ions. Thus, prolonged activation of glutamate receptors stimulates eNOS via Ca/CaM complex binding to the synthetase. The formation of NO is implicated in cell death as described above: DNA damage, suppressed mitochondrial respiration, leading to energy depletion. Neurons are particularly sensitive to impaired mitochondrial ATP synthesis capacity, because neurons depend almost exclusively on the oxidative degradation of glucose and ketone bodies. The formed ATP is used by ion selective pumps to maintain the proper ion gradients for action potential generation and neurotransmitter release of presynaptic membranes.
NO can only be synthesized, however, if the amino acid arginine is available. Neuronal NOS critically depends on this substrate, which is mainly synthesized in adjacent glial cells and is transported into neurons. Arginine uptake into neurons is controlled by non-NMDA glutamate receptors. This became evident when these receptors were blocked by arginine-uptake inhibitors such as L-lysine which functions as antagonist of these glutamate receptors. The physiological role of nNOS in mechanisms such as long term potentiation has been shown to involve retrograde transport (diffusion) of NO synthesized in post synaptic neurons across the synaptic cleft into synapses, where they stimulated guanyl cyclase. etc…
And of course there is much more on why ATP is affected by NOS / NO / SOD levels (see Martin Pall on the mechanism in MCS).
Do you know if Goldberg or Olin get into NOS in any serious way?
[Don’s reply: No. ]
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