Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Ann Neurol ; 88(2): 297-308, 2020 08.
Article in English | MEDLINE | ID: mdl-32418267

ABSTRACT

OBJECTIVE: Myotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and associated with side effects. Myotonia can be triggered by voluntary movement (electrically induced myotonia) or percussion (mechanically induced myotonia). Whether distinct molecular mechanisms underlie these triggers is unknown. Our goal was to identify ion channels involved in mechanically induced myotonia and to evaluate block of the channels involved as a novel approach to therapy. METHODS: We developed a novel system to enable study of mechanically induced myotonia using both genetic and pharmacologic mouse models of myotonia congenita. We extended ex vivo studies of excitability to in vivo studies of muscle stiffness. RESULTS: As previous work suggests activation of transient receptor potential vanilloid 4 (TRPV4) channels by mechanical stimuli in muscle, we examined the role of this cation channel. Mechanically induced myotonia was markedly suppressed in TRPV4-null muscles and in muscles treated with TRPV4 small molecule antagonists. The suppression of mechanically induced myotonia occurred without altering intrinsic muscle excitability, such that myotonia triggered by firing of action potentials (electrically induced myotonia) was unaffected. When injected intraperitoneally, TRPV4 antagonists lessened the severity of myotonia in vivo by approximately 80%. INTERPRETATION: These data demonstrate that there are distinct molecular mechanisms triggering electrically induced and mechanically induced myotonia. Our data indicates that activation of TRPV4 during muscle contraction plays an important role in triggering myotonia in vivo. Elimination of mechanically induced myotonia by TRPV4 inhibition offers a new approach to treating myotonia. ANN NEUROL 2020;88:297-308.


Subject(s)
Isometric Contraction/physiology , Morpholines/pharmacology , Myotonia Congenita/genetics , Myotonia Congenita/metabolism , Pyrroles/pharmacology , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/deficiency , Animals , Anthracenes/pharmacology , Isometric Contraction/drug effects , Mice , Mice, Knockout , Morpholines/therapeutic use , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiology , Myotonia Congenita/prevention & control , Pyrroles/therapeutic use
2.
Eur J Neurosci ; 42(2): 1830-8, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25865743

ABSTRACT

The suprachiasmatic nucleus (SCN) contains a circadian clock that generates endogenous rhythmicity and entrains that rhythmicity with the day-night cycle. The neurochemical events that transduce photic input within the SCN and mediate entrainment by resetting the molecular clock have yet to be defined. Because GABA is contained in nearly all SCN neurons we tested the hypothesis that GABA serves as this signal in studies employing Syrian hamsters (Mesocricetus auratus). Activation of GABAA receptors was found to be necessary and sufficient for light to induce phase delays of the clock. Remarkably, the sustained activation of GABAA receptors for more than three consecutive hours was necessary to phase-delay the clock. The duration of GABAA receptor activation required to induce phase delays would not have been predicted by either the prevalent theory of circadian entrainment or by expectations regarding the duration of ionotropic receptor activation necessary to produce functional responses. Taken together, these data identify a novel neurochemical mechanism essential for phase-delaying the 'master' circadian clock within the SCN as well as identifying an unprecedented action of an amino acid neurotransmitter involving the sustained activation of ionotropic receptors.


Subject(s)
Circadian Clocks/physiology , Light , Receptors, GABA-A/metabolism , Suprachiasmatic Nucleus/metabolism , Animals , Bicuculline/pharmacology , Circadian Clocks/drug effects , Cricetinae , Dose-Response Relationship, Drug , GABA Agents/pharmacology , Male , Mesocricetus , Microinjections , Muscimol/pharmacology , Reaction Time/drug effects , Suprachiasmatic Nucleus/drug effects , Time Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...