Molecular pharmacology
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The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation of this channel may be analgesic. Although several TRPA1 activators exist, these tend to be either reactive or of low potency and/or selectivity. The aim of the present study, therefore, was to identify novel TRPA1 agonists. ⋯ Farnesyl thiosalicylic acid activates the channel in excised patches and in the absence of calcium. Furthermore, using a quadruple TRPA1 mutant, we show that the mechanism of action of farnesyl thiosalicylic acid differs from that of the reactive electrophilic reagent allylisothiocyanate. As a TRPA1 agonist with a potentially novel mechanism of action, farnesyl thiosalicylic acid may be useful in the study of TRPA1 channels.
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Molecular pharmacology · Apr 2008
Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene.
Dantrolene is the drug of choice for the treatment of malignant hyperthermia (MH) and is also useful for treatment of spasticity or muscle spasms associated with several clinical conditions. The current study examines the mechanisms of dantrolene's action on skeletal muscle and shows that one of dantrolene's mechanisms of action is to block excitation-coupled calcium entry (ECCE) in both adult mouse flexor digitorum brevis fibers and primary myotubes. ⋯ We propose that this gain of ECCE function is an important etiological component of MH susceptibility and possibly contributes to the fulminant MH episode. The inhibitory potency of dantrolene on ECCE found in wild-type and MH-susceptible muscle is consistent with the drug's clinical potency for reversing the MH syndrome and is incomplete as predicted by its efficacy as a muscle relaxant.
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Molecular pharmacology · Apr 2008
Salicylate alters the expression of calcium response transcription factor 1 in the cochlea: implications for brain-derived neurotrophic factor transcriptional regulation.
Brain-derived neurotrophic factor (BDNF) is a key neurotrophin whose expression is altered in response to neurological activity, influencing both short- and long-term synaptic changes. The BDNF gene consists of eight upstream exons (I-VII), each of which has a distinct promoter and can be independently spliced to the ninth coding exon (IX). We showed recently that the expression of BDNF exon IV in the cochlea is altered after exposure to salicylate, an ototoxic drug that in high doses is able to induce hearing loss and tinnitus. ⋯ The changes in BDNF exon IV and CaRF1 expression were also dose-dependent. The data show Ca(2+) and CaRF1 as messengers of trauma (salicylate)-induced altered BDNF levels in the cochlea. Furthermore, they also provide the first evidence that a differential regulation of BDNF transcription factors might participate in BDNF-mediated plasticity changes.