International Journal of Nutrition, Pharmacology, Neurological Diseases

: 2015  |  Volume : 5  |  Issue : 4  |  Page : 128--134

Differential regulation of volatile anesthetics on ion channels

Senthilkumar Rajagopal, Supraj Raja Sangam, Shubham Singh 
 Department of Zoology, Nizam College, Hyderabad, Telangana, India

Correspondence Address:
Senthilkumar Rajagopal
Department of Zoology, Nizam College, Hyderabad - 500 001, Telangana


Pain processes are regulated by voltage-gated calcium channels (VDCC) and Ca2+. Many mediators of pain increase Ca2+ influx through calcium channels, leading to a significant increase in intracellular calcium ([Ca2+]i). Calcium channels act as integrators of G-protein-mediated signalling in neurons. Phosphorylation of calcium channels primary subunits by kinases such as protein kinase C (PKC) and tyrosine kinases have been shown to inhibit/enhance Cavchannels. Increased/decreased Cavcurrents and PKC activations observed in in vivo pain investigations, and a Xenopus oocytes model may serve as an in vitro model for some cellular mechanisms of pain. In this review, we focus on anesthetic and PKC regulations on ion channels and their properties.

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Rajagopal S, Sangam SR, Singh S. Differential regulation of volatile anesthetics on ion channels.Int J Nutr Pharmacol Neurol Dis 2015;5:128-134

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Rajagopal S, Sangam SR, Singh S. Differential regulation of volatile anesthetics on ion channels. Int J Nutr Pharmacol Neurol Dis [serial online] 2015 [cited 2021 Oct 16 ];5:128-134
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The term "anaesthesia" was coined by Oliver Wendell Holmes in 1846 to explain drug-induced insensibility to sensations, particularly pain, after the administration of ether given to a patient and inhaled, and the patient thus being unresponsive during a surgical procedure. These pharmacological agents are classified into two broad categories, local and general, and can result in anesthesia; in addition, the agents can produce insensibility to pain and loss of awareness.[1],[2],[3] Local anesthetics, such as Novocain, block nerve transmission to pain centers in the central nervous system (CNS) by binding to and inhibiting the function of an ion channel in the cell membrane of nerve cells, known as the sodium channel. This action obstructs the movement of nerve impulses near the site of injection, but there are no changes in awareness and sense perception in other areas. The potassium (K +) and calcium (Cav) channels are also affected by local anesthetics at clinically relevant concentrations in CNS.[4],[5],[6],[7],[8]

In contrast, general anesthetics induce a different kind of anesthetic state, and one element of it is insensibility to pain. The mechanism of action of general anesthetics is less known when compared to locals, despite their use for more than 150 years.[9],[10] General anesthetic agents are usually administered to be breathed in and are thus termed inhalational or volatile anesthetics. They are structurally related to ether, the original anesthetic. Their primary site of action is in the CNS, where they inhibit nerve transmission by a mechanism distinct from that of local anesthetics. The general anesthetics cause a reduction in nerve transmission at the synapses, the sites at which neurotransmitters are released and exert their initial action in the body. But precisely how inhalational anesthetics inhibit synaptic neurotransmission is not yet fully understood.[11],[12],[13] It is clear, however, that volatile anesthetics (VA), which are more soluble in lipids than in water, primarily affect the function of ion channel and neurotransmitter receptor proteins in the membranes of nerve cells, which are lipid environments.[14],[15]

There are two major factors that act as hurdles to obtaining the detailed mechanisms of anesthetic agents. First, volatile anesthetics bind only very weakly to their site(s) of action. As a result, high concentrations are needed to achieve an anesthetic state.[16],[17],[18] This makes it tricky to obtain the structural details of receptor (or protein) bound anesthetics. It is difficult to confirm the key mediators in anesthetic action, as it affects the function of many proteins in nerve cell membranes. Second, volatile anesthetics tend to partition into lipids and exert their primary effects on synaptic neurotransmission by interacting with proteins in a lipid environment.[19],[20],[21] It is harder to gain detailed structural information for membrane proteins than it is for water-soluble proteins. Such structural data are essential to understand the interaction of anesthetics with proteins and, more importantly, alter their function. Because of the lack of structural data for membrane proteins in both the presence and absence of anesthetics, it remains unclear whether anesthetics exert their primary effects by direct interaction with these proteins, or indirectly via interaction with the lipids surrounding them.[22],[23],[24]

 Molecular Targets of General Anesthetics

Ion channels have emerged as the most likely molecular targets for general anesthetics. Neurotransmitter-gated ion channels, in particular gamma-aminobutyric acid (GABA)A, glycine, and N-methyl-D-aspartate (NMDA)-type glutamate receptors, are leading candidates due to their appropriate CNS distributions, essential physiological roles in inhibitory and excitatory synaptic transmission, and sensitivities to clinically relevant concentrations of anesthetics.[25],[26],[27],[28]

The ability of general anesthetics to alter gene expression in the brain was first observed for the highly reactive acute early genes c-Fos and c-Jun.[29] Since then, multiple anesthetics have been observed to have effects on gene expression.[30] In the hippocampi of aged rats, changes in gene expression persisted for up to 2 days in rats exposed to isoflurane and nitrous oxide,[31] and changes in protein expression have been observed 3 days after exposure to desflurane.[32] The significance of these changes in gene and protein expression persisting after recovery from the classical signs of anesthesia remains to be established.

 Voltage-Gated Ion Channels as Targets of the Anesthetic Ligand-Gated Ion Channels

General anesthetics can act as either positive or negative allosteric modulators of ligand-gated ion channels at clinically effective concentrations.[25],[33] Most inhaled anesthetics, including all of the other anesthetics (e.g. isoflurane, sevoflurane, desflurane, and enflurane) and some of the alkanes (e.g. halothane), enhance GABAA receptor function by enhancing sensitivity to agonists and by directly opening channels in the absence of agonists at higher anesthetic concentrations. This increases channel-opening to enhance inhibition at both synaptic and extrasynaptic receptors. Recently, by using desflurane, an anesthetic binding site has been reported within a proton-activated pentameric ligand-gated ion channel of the cyanobacterium Gloeobacter violaceus (GLIC).[34] The inhaled anesthetics affect many receptors (e.g. GABAA, glycine, acetylcholine, serotonin, NMDA) in ways that could plausibly explain anesthesia. GABAB receptor is insensitive to the anesthetics. Clinically relevant concentrations of almost all inhalational and general anesthetics modulate the inhibitory GABA receptors, but ketamine and xenon are the exceptions.[35]

Na + channels

Evidence showing that mammalian voltage-gated Na + channels are sensitive to clinically relevant concentrations of general anesthetics has been gained from careful analysis of the anesthetic effects on channels expressed in heterologous fashion. Inhibition of presynaptic Na + channels has been implicated in the depression of evoked neurotransmitter release by volatile anesthetics from isolated nerve terminals and cultured rat hippocampus neurons.[36],[37] These findings identify presynaptic Na + channels as important anesthetic targets for potent inhaled anesthetics.[7]

Ca 2+ channels

Multiple cellular functions depend on the tightly controlled concentration of intracellular free Ca 2+, which is determined by the integrated activity of voltage-gated Ca 2+ channels, capacitative Ca 2+ channels, plasma membrane and endo/sarcoplasmic reticulum Ca 2+ -ATPases (pumps), Na +/Ca 2+ exchangers, and mitochondrial Ca 2+ sequestration.[38],[39],[40] Alteration of any of these mechanisms by anesthetics could affect the many cellular processes regulated by the second messenger actions of Ca 2+, which include synaptic transmission, gene expression, cytotoxicity, and muscle excitation-contraction coupling.[41],[42] Excitable cells translate electrical activity into action by Ca 2+ fluxes mediated primarily by voltage-gated Ca 2+ channels in the plasma membrane. There is convincing evidence that inhaled anesthetics inhibit some Ca 2+ channel isoforms, but not others.[43] Wheeler et al. showed that halothane decreased Ca 2+ release from the sarcoplasmic reticulum.[44] The role that inhibition of Ca 2+ channels plays in effects of anesthesia on the CNS is still not very clear.

The inhibitory activity of the isoflurane on CaV channel is already reported by the various research laboratories. Terrar and Victor showed that isoflurane depressed the inward calcium current and the amplitude of contraction in myocytes isolated from guinea-pig ventricles.[45] Isoflurane in clinically relevant concentration inhibited R-type CaV channels in brain slice preparations.[46] Clinically based depressants such as phenobarbital-inhibited P/Q-type Cav channels expressed in human embryonic kidney (HEK)-293 cells.[47] Some authors showed that protein kinase C (PKC)ε was translocated to the membrane after the administration of 0.4 minimum alveolar concentration (MAC) isoflurane, but not after 1.0 MAC or 1.75 MAC administration.[48] We investigated that isoflurane caused the translocation of PKCδ to the plasma membrane and converted Cav2.2 and Cav2.1 currents.[4] PKCδ with isoflurane potentiated Cav2.2 currents but the potentiation of the Cav2.2 currents by PKCε was not affected by the isoflurane. Both PMA and acetyl-β-methylcholine (MCh) failed to modulate Cav2.1 currents, but in the presence of isoflurane, PMA potentiated Cav2.1 currents and counteracted the typically depressant effect of isoflurane. Instead, MCh was unable to potentiate Cav2.1 currents when used in combination with isoflurane. The combination of PKCβII, PKCε, and isoflurane increased Cav2.1 currents exactly as was reported when PMA and isoflurane were used in combination. We concluded from our results that the inhibition of the Wild Type/control Cav2.2 currents produced by isoflurane seems to be due to direct actions on the channel combined with the actions of PKCδ on both the stimulatory and inhibitory PKC sites of the Cav2.2α1 subunit, but the binding of isoflurane at or near Ser-425 (inhibitory PKC phosphorylation site in the Cav2.2α1 subunit) is not possible, as polar hydrophilic amino acids (such as lysine, arginine, glutamate, and aspartate), are present, which is a typical sequence for the cytoplasmic tool.[4],[49] Rajagopal et al., showed that the complexity of combined direct and indirect actions of an anesthetic on an ion channel behavior and isoflurane-induced modulation of PKC activity could also have important consequences for other effector proteins and intracellular cascades. The PKC stimulatory sites in Cav2.2α1, i.e. Thr-422, Ser-1757, Ser-2108, and Ser-2132 seem to counteract the depressant effect of isoflurane observe in a wide variety of voltage-gated channels, while the inhibitory effect of isoflurane was augmented by the inhibitory site (Ser-425) in Cav2.2α1.[4]

The intercellular or intracellular transfer of information (biological activation/inhibition) takes place through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. The vital roles of voltage-gated calcium channels (VDCCs) are cell signalling, neurotransmitter release, and neuronal plasticity. Mutations in VDCC may result in severe chronic disorders, such as seizures, migraine, neurodegenerative disorders, and myasthenia syndromes.[50]

VDCC are a family of integral membrane calcium-sensitive proteins, which are presented in all excitable and many nonexcitable cells.[51] The cells can excites after cell depolarizng leads to calcium influx, affects membrane electrical properties. Calcium entry further regulates multiple intracellular signalling pathways as well as the biochemical factors that mediate physiological functions, such as neurotransmitter release and muscle contraction.[52] Small changes in the biophysical properties or expression of calcium channels can result in pathophysiological changes, leading to serious chronic disorders. In humans, mutations in calcium channel genes have been linked to a number of serious neurological, retinal, cardiac, and muscular disorders.[53]

Volatile anesthetics (VAs) are either decreased excitation, or enhanced inhibition, or the combination of these two that causes the reduction of synaptic transmission, and general anesthetics contribute to this reduction.[54] The increased intracellular Ca 2+ is mediated primarily synaptic transmission leading to vesicle fusion and transmitter release. The entry and exit of Ca 2+ from a cell is controlled by high voltage-activated (HVA) calcium channels.[55],[56] However, the activity of CaV is in part mediated by PKC isozymes.[57],[58] VAs altered the activity of both CaV and PKC, and isoflurane released presynaptically mediated neurotransmitters have been studied by multiple laboratories.[59],[60],[61] Isoflurane and other VAs have been shown to inhibit CaV channels in hippocampal neurons,[62] as well as when expressed in isolation in Xenopus oocytes.[63] Based on the sequence homology of the alpha1 subunit as well as their biophysical and pharmacological properties, these HVA channels are divided into two subfamilies: Cav1 (originally called L-type) and Cav2 (2.1, 2.2, and 2.3, aka P/Q-, N-, and R-types, respectively). Intracellular segments of the alpha1 subunit, viz., the N- and C- termini and the loops between domains I and II, II and III, and III and IV, possess binding/recognition sites for G-protein beta/gamma subunits, calmodulin, and phosphorylation sites for PKC isozymes.[64],[65],[66] The PKC family is divided into three subfamilies based on second messenger requirements for their activation, and it has at least 11 isozymes. Conventional PKCs (cPKCs: α, βI, βII, and γ) require Ca 2+, diacylglycerol (DAG), and phosphatidylserine. Novel PKCs (nPKC) include δ, ε, θ, and η isoforms, and require DAG, but not Ca 2+. Thus, cPKC and nPKCs can be activated through signal transduction pathways that activate phospholipase C (PLC). On the other hand, atypical PKCs (aPKC) ζ, µ, and ι/λ require neither Ca 2+ nor DAG,[67],[68] as VAs can alter Cav channel function as well as PKC activity.

 K + channels and HCN Channels

Potassium channels are an extremely diverse ion channel family noted for their varied modes of activation. They regulate electrical excitability, muscle contractility, and neurotransmitter release, and are important in determining the input resistance and in driving repolarization, and thus they determine excitability and action potential duration. Given the large diversity in K + channel structure, function, and anesthetic sensitivity, it is not surprising that there is considerable diversity in their sensitivity and response to anesthetics, from relatively insensitive to sensitive, resulting in inhibition, activation, or no effect on K + currents.[69],[70],[71]

Hydrogen cyanide (HCN) channels contribute to resting membrane potential; control action potential firing, dendritic integration, neuronal automaticity, and temporal summation; and determine the periodicity and synchronization of oscillations in many neuronal networks;[72] the anesthetic modulation of these channels could play an important role in anesthetic effects on neuronal integrative functions.[73]

 Intracellular Signalling Mechanims Affected by General Anesthetics

Cell signalling mechanisms are critical to all phases of organ function and have been attractive targets for the broad effects of general anesthetics. Anesthetics act in ways that are poorly understood on intracellular cell signalling pathways, which include processes downstream from cell surface receptors and ion channels, such as effects of second messengers, protein phosphorylation pathways, and other regulatory mechanisms.[74] A variety of signals, including hormones, neurotransmitters, cytokines, pheromones, odorants, and photons, produce their intracellular actions by interactions with metabotropic receptors that activate heterotrimeric guanine nucleotide (guanosine-5'-triphosphate or GTP)-binding proteins (G proteins). In contrast to the inotropic receptors that directly couple to ion-selective channels, G proteins act as indirect molecular switches to relay information from activated plasma membrane receptors to appropriate intracellular targets. Inhaled anesthetics can directly affect signalling via G protein-coupled receptors (GPCRs).[75] Phosphorylation of proteins on specific serine, threonine, or tyrosine hydroxyl groups, a posttranslational modification involved in the regulation of many anesthetic-sensitive receptors and ion channels, is pivotal to synaptic plasticity (e.g. long-term potentiating). Phosphorylation is controlled by the balance of activity between protein kinases and phosphatases, several of which are plausible anesthetic targets. Potent inhaled anesthetics enhance the activity of specific PKC isoforms and stimulate the phosphorylation of specific PKC substrates.[76] A specific role for a direct, pharmacologically relevant effect mediated by anesthetic activation of PKC or of any other kinase has yet to be demonstrated. Additional studies will be required to determine which anesthetic effects on kinase pathways represent direct effects, as occurs with PKC, and which effects are indirect and due to anesthetic-induced alterations in signalling molecules known to regulate protein kinase and phosphatase activity, such as Ca 2+ and other second messengers.

Although some investigators have suggested that PKC-dependent pathways might play a role in the biochemical mechanism producing spinal anesthesia, there is no correlation between changes in PKC levels and either the potency or lipid solubility of the anesthetics.[77] In immunohistochemical experiments, activation of the mitogen-activated protein (MAP) kinase extracellular receptor-activated kinase in dorsal horn neurons of the spinal cord by the PKC activator phorbol 12-myristate 13-acetate (PMA) was insensitive to bupivacaine, although bupivacaine did inhibit the activation of extracellular-signal-regulated kinase (ERK) stimulated by several inotropic receptors.[78],[79] Such findings indicate that the action of bupivacaine occurred neither at PKC itself nor at sites downstream toward ERK. The discrepancy between the results on purified PKC and the enzyme's effects in situ could be explained by a differential sensitivity of different PKC isozymes to local anesthetics or to drug sensitivities that depend on the cofactors for enzyme activation.[4],57,[80],[81],[82],[83] Thus, particular PKC isozymes may be direct biochemical targets for local anesthetic action, but other sites of local anesthetics may be located along the upstream pathway that activates PKC.


In summary, the current understanding of the molecular mechanisms of volatile anesthetics will not be complete until we understand how the calcium channels alter the configuration of their protein folding. In addition, with regard to the anesthetic-induced modulation of PKC activity described here, we should learn, in the coming years, a great deal more about the molecular mechanisms of other effector proteins and intracellular cascades.


This work was supported by the Department of Biotechnology, Ministry of Science and Technology, Government of India to Senthilkumar Rajagopal. The content is solely the responsibility of the authors and does not necessarily represent the views of the Department of Biotechnology, Govt. of India.

Financial support and sponsorship

This work was supported by the Department of Biotechnology, Ministry of Science and Technology, Government of India to R.S.

Conflicts of interest

No conflicts of interest, financial or otherwise, are declared by the author(s).


1Garcia PS, Kolesky SE, Jenkins A. General anaesthetic actions on GABAA receptors. Curr Neuropharmacol 2010;8:2-9.
2Fitz-Henry J. The ASA classification and peri-operative risk. Ann R Coll Surg Engl 2011;93:185-7.
3Reddy S, Patt RB. The benzodiazepines as adjuvant analgesics. J Pain Symptom Manage 1994;9:510-4.
4Rajagopal S, Fang H, Lynch C 3rd, Sando JJ, Kamatchi GL. Effects of Isoflurane on the expressed Cav2.2 currents in Xenopus oocytes depend on the activation of protein kinase Cδ and its phosphorylation sites in the Cav2.2α1 Subunits. Neurosci 2011;182:232-40.
5Scholz A. Mechanism of (local) anaesthetics on voltage-gated sodium and other ion channels. Br J Anaesth2002;89:52-61.
6Gissen AJ, Covino BG, Gregus J. Differential sensitivities of mammalian nerve fibers to local anesthetic agents. Anesthesiology 1980;53:467-74.
7Hemmings HC Jr. Sodium channels and the synaptic mechanisms of inhaled anaesthetics. Br J Anaesth 2009;103:61-9.
8Lingamaneni R, Hemmings HC Jr. Differential interaction of anaesthetics and antiepileptic drugs with neuronal Na + channels, Ca2 + channels, and GABA (A) receptors. Br J Anaesth 2003;90:199-211.
9Franks NP, Lieb WR. Temperature dependence of the potency of volatile general anaesthetics: Implications for in vitro experiments. Anesthesiology 1996;84:716-20.
10Li X, Pearce RA. Effects of halothane on GABA (A) receptor kinetics: Evidence for slowed agonist unbinding. J Neurosci 2000;20:899-907.
11Harrison NL, Simmonds MA. Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br J Pharmacol1985;84:381-91.
12Bergendahl H, Lönnqvist PA, Eksborg S. Clonidine in paediatric anaesthesia: Review of the literature and comparison with benzodiazepines for anaesthetic premedication. Acta Anaesthesiol Scand 2006;50:135-43.
13Hewer CL. The stages and signs of general anaesthesia. Br Med J 1937;2:274-6.
14Chiao S, Zuo Z. A double-edged sword: Volatile anaesthetic effects on the neonatal brain. Brain Sci 2014;4:273-94.
15Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci 2003;28:263-74.
16Eckenhoff RG, Johansson JS. Molecular interactions between inhaled anaesthetics and proteins. Pharmacol Rev1997;49:343-67.
17Becker DE, Rosenberg M. Nitrous oxide and inhalation anaesthetics. Anesth Prog2008;55:124-32.
18Liu R, Loll PJ, Eckenoff RG. Structural basis for high-affinity volatile anesthetic binding in a natural 4-helix bundle protein. FASEB J 2005;19:567-76.
19Eger EI 2nd, Saidman LJ, Brandstater B. Temperature dependence of halothane and cyclopropane anaesthesia in dogs: Correlation with some theories of anesthetic action. Anesthesiology 1965;26:764-70.
20Franks NP, Lieb WR. Do general anaesthetics act by competitive binding to specific receptors? Nature 1984;310:599-601.
21Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994;367:607-14.
22Tsuchiya H, Mizogami M. Comparative interactions of anaesthetic alkylphenols with lipid membranes. Open J Anesthesiol 2014;4:308-17.
23Tsuchiya H. Structure-specific membrane-fluidizing effect of propofol. Clin Exp Pharmacol Physiol 2001;28:292-9.
24Gutiérrez ME, García AF, Africa de Madariaga M, Sagrista ML, Casadó FJ, Mora M. Interaction of tocopherols and phenolic compounds with membrane lipid components: Evaluation of their antioxidant activity in a liposomal model system. Life Sci 2003;72:2337-60.
25Yamakura T, Bertaccini E, Trudell JR, Harris RA. Anesthetics and ion channels: Molecular models and sites of action. Annu Rev Pharmacol Toxicol 2001;41:23-51.
26Sonner JM, Antognini JF, Dutton RC, Flood P, Gray AT, Harris RA, et al. Inhaled anesthetics and immobility: Mechanisms, mysteries, and minimum alveolar anesthetic concentration. Anesthe Analg 2003;97:718-40.
27Rudolph U, Antkowiak B. Molecular and neuronal substrates for general anesthetics. Nat Rev Neurosci 2004;5:709-20.
28Hemmings HC Jr, Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL. Emerging molecular mechanisms of general anesthetic action. Trends Pharamacol Sci 2005;26:503-10.
29Munglani R, Hunt SP. Molecular biology of pain. Br J Anaesth1995;75:186-92.
30Perouansky M, Hemmings HC Jr. Neurotoxicity of genral anesthetics: Cause for concern? Anesthesiology 2009;111:1365-71.
31Culley DJ, Baxter MG, Yukhananov R, Crosby G. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats. Anesthesiology 2004;100:309-14.
32Hogan K. Long-lasting changes in brain protein expression after exposure to an anesthetic. Anesthesiology 2004;100:209-12.
33Krasowski MD, Harrison NL. General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci 1999;55:1278-303.
34Nury H, Van Renterghem C, Weng Y, Tran A, Baaden M, Dufresne V, et al. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 2011;469:428-31.
35Weir CJ. The molecular mechanisms of general anaesthesia: Dissecting the GABAA receptor. Contin Educ Anaesth Crit Care Pain 2006;6:49-53.
36Westphalen RI, Hemmings HC Jr. Selective depression by general anesthetics of gluatamate versus GABA release from isolated cortical nerve terminals. J Pharmacol Exp Ther 2003;304:1188-96.
37Hemmings HC Jr, Yan W, Westphalen RI, Ryan TA. The general anaesthetic isoflurane depresses synaptic vesicle exocytosis. Mol Pharmacol 2005;67:1591-9.
38Barritt GJ. Receptor-activated Ca2+ inflow in animal cells: A variety of pathways tailored to meet different intracellular Ca2+ signalling requirements. Biochem J1999;337:153-69.
39Clapham DE. Calcium signaling. Cell 1995;80:259-68.
40Putney JW Jr. Calcium signaling: Up, down, up, down. What's the point? Science 1998;279:191-2.
41Meir A, Ginsburg S, Butkevich A, Kachalsky SG, Kaiserman I, Ahdut R, et al. Ion channels in presynaptic nerve terminals and control of transmitter release. Physiol Rev1999;79:1019-88.
42Fozzard HA, Hanck DA. Structure and function of voltage-dependent sodium channels: Comparison of brain II and cardiac isoforms. Physiol Rev 1996;76:887-926.
43Topf N, Recio-Pinto E, Blanck T, Hemmings HJ. Actions of general anesthetics on voltage-gated ion channels. In: Antognini J, Carlens E, Raines D, editors. Neural Mechanisms of Anesthesia. Totowa, NJ: Humana Press; 2003. p. 299-318.
44Wheeler DM, Rice RT, Hansford RG, Lakatta EG. The effect of halothane on the free intracellular calcium concentration of isolated rat heart cells. Anesthesiology 1988;69:578-83.
45Terrar DA, Victory JG. Isoflurane depresses membrane currents associated with contraction in myocytes isolated from guinea-pig ventricle. Anesthesiology 1988;69:742-9.
46Joksovic PM, Weiergräber M, Lee W, Struck H, Schneider T, Todorovic SM. Isoflurane-sensitive presynaptic R-type calcium channels contribute to inhibitory synaptic transmission in the rat thalamus. J Neurosci 2009;29:1434-45.
47Schober A, Sokolova E, Gingrich KJ. Phenobarbital inhibition of human recombinant alpha1A P/Q-type voltage-gated calcium channels involves slow, open channel block. Br J Pharmacol 2010;161:365-83.
48Obal D, Weber NC, Zacharowski K, Toma O, Dettwiler S, Wolter JI, et al. Role of protein kinase C-epsilon (PKCepsilon) in isoflurane-induced cardioprotection. Br J Anaesth 2006;94:166-73.
49Lin Z, Haus S, Edgerton J, Lipscombe D. Identification of functionally distinct isoforms of the N-type Ca2+ channel in rat sympathetic ganglia and brain. Neuron 1997;18:153-66.
50Striessnig J, Bolz HJ, Koschak A. Channelopathies in Cav1.1, Cav1.3 and Cav1.4 voltage-gated L-type Ca2+ channels. Pflugers Arch 2010;460:361-74.
51Cain SM, Snutch TP. Voltage-gated calcium channels and disease. Biofactors 2011;37:197-205.
52Zündorf G, Reiser G. Calcium dysregulation and homeostasis of neural calcium in the molecular mechanisms of neurodegenerative diseases provide multiple targets for neuroprotection. Antioxid Redox Signal 2011;14:1275-88.
53Adams PJ, Snutch TP. Calcium channelopathies: Voltage-gated calcium channels. Subcell Biochem 2007;45:215-51.
54Richards CD. What the actions of anaesthetics on fast synaptic transmission reveal about the molecular mechanism of anaesthesia. Toxicol Lett 1998;100-101:41-50.
55Dolphin AC. Calcium channel diversity: Multiple roles of calcium channel subunits. Curr Opin Neurobiol 2009;19:237-44.
56Catterall WA. Signalling complexes of voltage-gated sodium and calcium channels. Neurosci Lett 2010;486:107-16.
57Rajagopal S, Fang H, Oronce CI, Jhaveri S, Taneja S, Dehlin EM, et al. Site-specific regulation of CA (V) 2.2 channels by protein kinase C isozymes betaII and epsilon. Neuroscience 2009;159:618-28.
58Rajagopal S, Fang H, Patanavanich S, Sando JJ, Kamatchi GL. Protein kinase C isozyme-specific potentiation of expressed Ca v 2.3 currents by acetyl-beta-methylcholine and phorbol-12-myristate, 13-acetate. Brain Res 2008;1210:1-10.
59Larsen M, Grøndahl TO, Haugstad TS, Langmoen IA. The effect of the volatile anesthetic isoflurane on Ca (2+)-dependent glutamate release from rat cerebral cortex. Brain Res 1994;663:335-7.
60Mantz J, Varlet C, Lecharny JB, Henzel D, Lenot P, Desmonts JM. Effects of volatile anesthetics, thiopental, and ketamine on spontaneous and depolarization-evoked dopamine release from striatal synaptosomes in the rat. Anesthesiology 1994;80:352-63.
61Miao N, Frazer MJ, Lynch C 3rd. Anesthetic actions on calcium uptake and calcium-dependent adenosine triphosphatase activity of cardiac sarcoplasmic reticulum. Adv Pharmacol 1994;31:145-65.
62Study RE. Isoflurane inhibits multiple voltage-gated calcium currents in hippocampal pyramidal neurons. Anesthesiology 1994;81:104-16.
63Kamatchi GL, Chen CK, Snutch T, Durieux ME, Lynch C 3rd. Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes. Brain Res 1999;831:85-96.
64Melliti K, Meza U, Adams B. Muscarinic stimulation of alpha1E Ca channels is selectively blocked by the effector antagonist function of RGS2 and phospholipase C-beta1. J Neurosci 2000;20:7167-73.
65Kamatchi GL, Franke R, Lynch C 3rd, Sando JJ. Identification of sites responsible for potentiation of type 2.3 calcium currents by acetyl-beta-methylcholine. J Biol Chem 2004;279:4102-9.
66Fang H, Franke R, Patanavanich S, Lalvani A, Powell NK, Sando JJ, et al. Role of alpha1 2.3 subunit I-II linker sites in the enhancement of Ca (v) 2.3 currents by phorbol 12-myristate 13-acetate and acetyl-beta-methylcholine. J Biol Chem 2005;280:23559-65.
67Newton AC. Diacylglycerol's affair with protein kinase C turns 25. Trends Pharmacol Sci2004;25:175-7.
68Newton AC. Protein kinase C: Poised to signal. Am J Physiol Endocrinol Metab 2010;298:E395-402.
69Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks NP. Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol 2004;65:443-52.
70Friederich P, Benzenberg D, Trellakis S, Urban BW. Interaction of volatile anesthetics with human Kv channels in relation to clinical concentrations. Anesthesiology 2001;95:954-8.
71Hille B. Potassium Channels and Chloride Channels. Ion Channels of Excitable Membranes. Sunderland, Mass: Sinauer; 2001. p. 131-68.
72Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: From molecules to physiological function. Annu Rev Physiol 2003;65:453-80.
73Postea O, Biel M. Exploring HCN channels as novel drug targets. Nat Rev Drug Discov 2011;10:903-14.
74Girault J, Hemmings HJ. Cell signaling. In: Hemmings HJ, Hopkins P, editors. Foundations of Anesthesia: Basic Sciences for Clinical Practice. London: Mosby Elsevier; 2006. p. 31-50.
75Rebecchi MJ, Pentyala SN. Anaesthetic actions on other targets: Protein kinase C and guanine nucleotide-binding proteins. Br J Anaesth 2002;89:62-78.
76Gomez R, Guatimosim C, Gomez MV. Mechanism of action of volatile anesthetics: Role of protein kinase C. Cell Mol Neurobiol 2003;23:877-85.
77Nivarthi RN, Grant GJ, Turndorf H, Bansinath M. Spinal anesthesia by local anesthetics stimulates the enzyme protein kinase C and induces the expression of an immediate early oncogene, c-Fos. Anesth Analg 1996;83:542-7.
78Hasegawa J, Takekoshi S, Nagata H, Osamura RY, Suzuki T. Sevoflurane stimulates MAP kinase signal transduction through the activation of PKC alpha and betaII in fetal rat cerebral cortex cultured neuron. Acta Histochem Cytochem 2006;39:163-72.
79Zhong L, Su JY. Isoflurane activates PKC and Ca (2+) -calmodulin-dependent protein kinase II via MAP kinase signaling in cultured vascular smooth muscle cells. Anesthesiology 2002;96:148-54.
80Rajagopal S, Fang H, Lynch C 3rd, Kamatchi GL. Formalin-induced short- and long-term modulation of Cav currents expressed in Xenopus oocytes: An in vivo cellular model for formalin-induced pain. Basic Clin Pharmacol Toxicol 2010;106:338-47.
81Singh S, Sangam SR, Joginapally VR Rajagopal S. Alcohol, glycine and gastritis. Int J Nutr Pharmacol Neurol Dis 2015;5:1-5.
82Guest JA, Grant RS. Effects of dietary derived antioxidants on the central nervous system. Int J Nutr Pharmacol Neurol Dis 2012;2:185-97.
83Veerappan R, Senthilkumar R. Chrysin enhances antioxidants and oxidative stress in L-NAME-induced hypertensive rats. Int J Nutr Pharmacol Neurol Dis 2015;5:20-7.