Amino acids in transmembrane domain two influence anesthetic enhancement of serotonin-3A receptor function

Lopreato, Gregory F.; Banerjee, Paula; Mihic, S. John

doi:10.1016/s0169-328x(03)00332-2

Cited by 20 publications

(13 citation statements)

References 18 publications

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“…This is consistent with results of a number of studies on other neurotransmitter‐gated ion channels showing different sites of action of ethanol and various sedative‐hypnotic agents and anaesthetics (Mihic et al. , 1997; Krasowski and Harrison, 2000; Lopreato et al. , 2003; Bali and Akabas, 2004; Schofield and Harrison, 2005; Yevenes et al.…”

Section: Discussionsupporting

confidence: 91%

Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit

Salous

Ren

Lamb

et al. 2009

British J Pharmacology

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Section: Discussionsupporting

confidence: 91%

Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit

Salous

Ren

Lamb

et al. 2009

British J Pharmacology

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“…Alternatively, the binding site may be present within the h5-HT 3A subunit itself and may be absent within the h5-HT 3B subunit. A recent study described dramatic changes in the modulation of 5-HT-mediated currents by volatile anesthetics by mutating leucine (L)270, the 15Ј residue within TM2 of the murine 5-HT 3A receptor (Lopreato et al, 2003). The L270 residue is homologous to the glycine receptor ␣1 serine (S)267 and GABA A ␣1 S270 residues that are known to be important for the enhancement by volatile anesthetics and alcohols on those receptors (Mihic et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…The L270 residue is homologous to the glycine receptor ␣1 serine (S)267 and GABA A ␣1 S270 residues that are known to be important for the enhancement by volatile anesthetics and alcohols on those receptors (Mihic et al, 1997). Lopreato et al (2003) proposed that L270 of the murine 5-HT 3A subunits is important for the effects of anesthetics and alcohols and may even form the hydrophobic pocket that is the binding site. Interestingly, the 15Ј residue in the TM2 of h5-HT 3A is also a leucine, whereas the h5-HT 3B subunits have an arginine.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Stevens¹,

Rüsch²,

Solt³

et al. 2005

J Pharmacol Exp Ther

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Functional 5-hydroxytryptamine type 3 (5-HT 3 ) receptors can be formed by 5-HT 3A subunits alone or in combination with the 5-HT 3B subunit, but only the 5-HT 3A receptor has been previously studied with respect to the modulation by volatile anesthetics and n-alcohols. Using two-electrode voltage-clamp, we show for the first time the modulation of heteromeric human (h)5-HT 3AB receptors, expressed in Xenopus oocytes, by a series of n-alcohols and halogenated volatile anesthetics. At twice their anesthetic concentration, compounds having a molecular volume of less than 110 Å 3 enhanced submaximal 5-HTevoked current. Compounds larger than 110 Å 3 inhibited submaximal 5-HT-evoked current. In experiments examining 5-HT concentration-response relationships, chloroform and butanol caused a slight decrease in the 5-HT EC 50 . Sevoflurane and octanol inhibited 5-HT-evoked current at all 5-HT concentrations tested but had no effect upon the 5-HT EC 50 . Compared with previous data on homomeric h5-HT 3A receptors, the presence of the h5-HT 3B subunit reduces the enhancement of h5-HT 3 receptors by smaller halogenated volatile anesthetics and n-alcohols. In summary, these results suggest that heteromeric h5-HT 3AB receptors are modulated by halogenated volatile anesthetics at clinically relevant concentrations, in addition to n-alcohols, suggesting that these receptors may be another physiological target for these compounds. The modulation is dependent upon the molecular volume of the compound, further supporting the concept of an anesthetic binding pocket of limited volume common on other Cys-loop ligand-gated ion channels. Incorporation of the 5-HT 3B subunit alters either the anesthetic binding site or the allosteric interactions between anesthetic binding and channel opening.

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“…Instead, these complex VOC effects suggest that these compounds interfere with VSCC gating and voltage sensing. In ligand-gated ion channels, transmembrane regions are important for interactions of ethanol, volatile anesthetics, and to a lesser extent VOCs (Krasowski and Harrison, 2000;Ronald et al, 2001;Lopreato et al, 2003a). The fourth membrane-spanning region of the ␣ subunit of VSCCs contains highly conserved residues responsible for sensing membrane voltage (Franciolini, 1994).…”

Section: Discussionmentioning

confidence: 99%

Perturbation of Voltage-Sensitive Ca²⁺ Channel Function by Volatile Organic Solvents

Shafer¹,

Bushnell²,

Benignus³

et al. 2005

J Pharmacol Exp Ther

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The mechanisms underlying the acute neurophysiological and behavioral effects of volatile organic compounds (VOCs) remain to be elucidated. However, the function of neuronal ion channels is perturbed by VOCs. The present study examined effects of toluene (TOL), trichloroethylene (TCE), and perchloroethylene (PERC) on whole-cell calcium current (I Ca ) in nerve growth factor-differentiated pheochromocytoma (PC12) cells. All three VOCs affected I Ca in a reversible, concentration-dependent manner. At ϩ10-mV test potentials, VOCs inhibited I Ca , whereas at test potentials of Ϫ20 and Ϫ10 mV, they potentiated it. The order of potency for inhibition (IC 50 ) was PERC (270 M) Ͼ TOL (720 M) Ͼ TCE (1525 M). VOCs also changed I Ca inactivation kinetics from a single-to double-exponential function. Voltage-ramp experiments suggested that VOCs shifted I Ca activation in a hyperpolarizing direction; this was confirmed by calculating the half-maximal voltage of activation (V 1/2, act ) in the absence and presence of VOCs using the Boltzman equation. V 1/2, act was shifted from approximately Ϫ2 mV in control to Ϫ11, Ϫ12, and Ϫ16 mV by TOL, TCE, and PERC, respectively. Similarly, VOCs shifted the half-maximal voltage of steady-state inactivation (V 1/2, inact ) from approximately Ϫ16 mV in control to Ϫ32, Ϫ35, and Ϫ20 mV in the presence of TOL, TCE, and PERC, respectively. Inhibition of I Ca by TOL was confirmed in primary cultures of cortical neurons, where 827 M TOL inhibited current by 61%. These data demonstrate that VOCs perturb voltage-sensitive Ca 2ϩ channel function in neurons, an effect that could contribute to the acute neurotoxicity of these compounds.Volatile organic compounds (VOCs), such as toluene (

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Amino acids in transmembrane domain two influence anesthetic enhancement of serotonin-3A receptor function

Cited by 20 publications

References 18 publications

Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit

Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Perturbation of Voltage-Sensitive Ca²⁺ Channel Function by Volatile Organic Solvents

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Amino acids in transmembrane domain two influence anesthetic enhancement of serotonin-3A receptor function

Cited by 20 publications

References 18 publications

Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit

Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit

Modulation of Human 5-Hydroxytryptamine Type 3AB Receptors by Volatile Anesthetics and n-Alcohols

Perturbation of Voltage-Sensitive Ca2+ Channel Function by Volatile Organic Solvents

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Perturbation of Voltage-Sensitive Ca²⁺ Channel Function by Volatile Organic Solvents