Effects of Alcohols and Anesthetics on Recombinant Voltage-Gated Na<sup>+</sup> Channels

Shiraishi, Munehiro; Harris, R. Adron

doi:10.1124/jpet.103.064063

Cited by 68 publications

(85 citation statements)

References 44 publications

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“…The fast voltage-gated Na ϩ channel-mediated spike was unaffected by EtOH, in agreement with the literature indicating that these channels are insensitive to subanesthetic EtOH concentrations (Shiraishi and Harris, 2004). This finding also indicates that EtOH does not affect AMPARs, which are responsible for initiating the CS (Schmolesky et al, 2002).…”

Section: Etoh Does Not Modulate the Initial Phase Of The Cssupporting

confidence: 79%

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Carta¹,

Mameli²,

Valenzuela³

2006

J. Neurosci.

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Consumption of alcoholic beverages produces alterations in motor coordination and equilibrium that are responsible for millions of accidental deaths. Studies indicate that ethanol produces these alterations by affecting the cerebellum, a brain region involved in the control of motor systems. Purkinje neurons of the cerebellar cortex have been shown to be particularly important targets of ethanol. However, its mechanism of action at these neurons is poorly understood. We hypothesized that ethanol could modulate Purkinje neuron function by altering the excitatory input provided by the climbing fiber from the inferior olive, which evokes a powerful all-or-none response denoted as the complex spike. To test this hypothesis, we performed whole-cell patch-clamp electrophysiological and Ca 2ϩ imaging experiments in acute slices from rat cerebella. We found that ethanol potently inhibits the late phase of the complex spike and that this effect is the result of inhibition of type-1 metabotropic glutamate receptor-dependent responses at the postsynaptic level. Moreover, ethanol inhibited climbing fiber long-term depression, a form of synaptic plasticity that also depends on activation of these metabotropic receptors. Our findings identify the climbing fiber3 Purkinje neuron synapse as an important target of ethanol in the cerebellar cortex and indicate that ethanol significantly affects cerebellar circuits even at concentrations as low as 10 mM (legal blood alcohol level in the United States is below 0.08 g/dl ϭ 17 mM).

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Section: Etoh Does Not Modulate the Initial Phase Of The Cssupporting

confidence: 79%

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Carta¹,

Mameli²,

Valenzuela³

2006

J. Neurosci.

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“…We have shown in earlier experiments that TTX fully blocks all I Na . Hexanol, one of the n-alcohols known to block I NaT (Horishita and Harris 2008;Shiraishi and Harris 2004) and to have anesthetic effects (Alifimoff et al 1989), was chosen because of its strong potency with relatively low concentration compared with other alcohols with a shorter carbon chain such as ethanol and butanol. Hexanol at 2.8 mM (a moderate anesthetic concentration) suppressed both I NaS and I NaT , but to different degrees.…”

Section: Resultsmentioning

confidence: 99%

“…Hexanol, riluzole, and ranolazine were used to investigate the pharmacology of I NaS . The n-alcohols are well-known I NaT blockers (Horishita and Harris 2008;Shiraishi and Harris 2004), but their effect on I NaS is not known. In our results, the differential blocking of the drug on I NaT and I NaS (Fig.…”

Section: Discussionmentioning

confidence: 99%

Slowly inactivating component of Na⁺ current in peri-somatic region of hippocampal CA1 pyramidal neurons

Park

Johnston

Gray

2013

Journal of Neurophysiology

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Park YY, Johnston D, Gray R. Slowly inactivating component of Na ϩ current in peri-somatic region of hippocampal CA1 pyramidal neurons. J Neurophysiol 109: 1378 -1390, 2013. First published December 12, 2012 doi:10.1152/jn.00435.2012.-The properties of voltage-gated ion channels on the neuronal membrane shape electrical activity such as generation and backpropagation of action potentials, initiation of dendritic spikes, and integration of synaptic inputs. Subthreshold currents mediated by sodium channels are of interest because of their activation near rest, slow inactivation kinetics, and consequent effects on excitability. Modulation of these currents can also perturb physiological responses of a neuron that might underlie pathological states such as epilepsy. Using nucleated patches from the peri-somatic region of hippocampal CA1 neurons, we recorded a slowly inactivating component of the macroscopic Na ϩ current (which we have called I NaS ) that shared many biophysical properties with the persistent Na ϩ current, I NaP , but showed distinctively faster inactivating kinetics. Ramp voltage commands with a velocity of 400 mV/s were found to elicit this component of Na ϩ current reliably. I NaS also showed a more hyperpolarized I-V relationship and slower inactivation than those of the fast transient Na ϩ current (I NaT ) recorded in the same patches. The peak amplitude of I NaS was proportional to the peak amplitude of I NaT but was much smaller in amplitude. Hexanol, riluzole, and ranolazine, known Na ϩ channel blockers, were tested to compare their effects on both I NaS and I NaT . The peak conductance of I NaS was preferentially blocked by hexanol and riluzole, but the shift of half-inactivation voltage (V 1/2 ) was only observed in the presence of riluzole. Current-clamp measurements with hexanol suggested that I NaS was involved in generation of an action potential and in upregulation of neuronal excitability.

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“…The specific neuronal Na ϩ channel isoform(s) affected by isoflurane in cultured hippocampal neurons is not known. All major adult CNS Na ϩ channel isoforms are inhibited by isoflurane (Shiraishi and Harris, 2004); the sensitivities of neonatal splicing variants are unknown.…”

Section: Discussionmentioning

confidence: 99%

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

Hemmings¹,

Yan²,

Westphalen³

et al. 2005

Mol Pharmacol

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General anesthetics have marked effects on synaptic transmission, but the mechanisms of their presynaptic actions are unclear. We used quantitative laser-scanning fluorescence microscopy to analyze the effects of the volatile anesthetic isoflurane on synaptic vesicle cycling in cultured neonatal rat hippocampal neurons monitored using either transfection of a pH-sensitive form of green fluorescent protein fused to the luminal domain of VAMP (vesicle-associated membrane protein), (synapto-pHluorin) or vesicle loading with the fluorescent dye FM 1-43. Isoflurane reversibly inhibited action potentialevoked exocytosis over a range of concentrations, with little effect on vesicle pool size. In contrast, exocytosis evoked by depolarization in response to an elevated extracellular concentration of KCl, which is insensitive to the selective Na ϩ channel blocker tetrodotoxin, was relatively insensitive to isoflurane.Inhibition of exocytosis by isoflurane was resistant to bicuculline, indicating that this presynaptic effect is not caused by the well known GABA A receptor modulation by volatile anesthetics. Depression of exocytosis was mimicked by a reduction in stimulus frequency, suggesting a reduction in action potential initiation, conduction, or coupling to Ca 2ϩ channel activation. There was no evidence for a direct effect on endocytosis. The effects of isoflurane on synaptic transmission are thus caused primarily by inhibition of action potential-evoked synaptic vesicle exocytosis at a site upstream of Ca 2ϩ entry and exocytosis, possibly as a result of Na ϩ channel blockade and/or K ϩ channel activation, with the possibility of lesser contributions from Ca 2ϩ channel blockade and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated vesicle fusion.

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Effects of Alcohols and Anesthetics on Recombinant Voltage-Gated Na⁺ Channels

Abstract: Voltage-gated Na ϩ channels (Na ϩ channels) mediate the rising phase of action potentials in neurons and excitable cells. Nine subtypes of the ␣ subunit (Na v 1

Cited by 68 publications

References 44 publications

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Slowly inactivating component of Na⁺ current in peri-somatic region of hippocampal CA1 pyramidal neurons

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

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Effects of Alcohols and Anesthetics on Recombinant Voltage-Gated Na+ Channels

Abstract: Voltage-gated Na ϩ channels (Na ϩ channels) mediate the rising phase of action potentials in neurons and excitable cells. Nine subtypes of the ␣ subunit (Na v 1

Cited by 68 publications

References 44 publications

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Slowly inactivating component of Na+ current in peri-somatic region of hippocampal CA1 pyramidal neurons

The General Anesthetic Isoflurane Depresses Synaptic Vesicle Exocytosis

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Effects of Alcohols and Anesthetics on Recombinant Voltage-Gated Na⁺ Channels

Slowly inactivating component of Na⁺ current in peri-somatic region of hippocampal CA1 pyramidal neurons