|Title||Sodium channels as targets for volatile anesthetics.|
|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Herold KF, Hemmings HC|
The molecular mechanisms of modern inhaled anesthetics are still poorly understood although they are widely used in clinical settings. Considerable evidence supports effects on membrane proteins including ligand- and voltage-gated ion channels of excitable cells. Na(+) channels are crucial to action potential initiation and propagation, and represent potential targets for volatile anesthetic effects on central nervous system depression. Inhibition of presynaptic Na(+) channels leads to reduced neurotransmitter release at the synapse and could therefore contribute to the mechanisms by which volatile anesthetics produce their characteristic end points: amnesia, unconsciousness, and immobility. Early studies on crayfish and squid giant axon showed inhibition of Na(+) currents by volatile anesthetics at high concentrations. Subsequent studies using native neuronal preparations and heterologous expression systems with various mammalian Na(+) channel isoforms implicated inhibition of presynaptic Na(+) channels in anesthetic actions at clinical concentrations. Volatile anesthetics reduce peak Na(+) current (I(Na)) and shift the voltage of half-maximal steady-state inactivation (h(∞)) toward more negative potentials, thus stabilizing the fast-inactivated state. Furthermore recovery from fast-inactivation is slowed, together with enhanced use-dependent block during pulse train protocols. These effects can depress presynaptic excitability, depolarization and Ca(2+) entry, and ultimately reduce transmitter release. This reduction in transmitter release is more potent for glutamatergic compared to GABAergic terminals. Involvement of Na(+) channel inhibition in mediating the immobility caused by volatile anesthetics has been demonstrated in animal studies, in which intrathecal infusion of the Na(+) channel blocker tetrodotoxin increases volatile anesthetic potency, whereas infusion of the Na(+) channels agonist veratridine reduces anesthetic potency. These studies indicate that inhibition of presynaptic Na(+) channels by volatile anesthetics is involved in mediating some of their effects.
|Alternate Journal||Front Pharmacol|
|PubMed Central ID||PMC3316150|
|Grant List||R01 GM058055 / GM / NIGMS NIH HHS / United States|