Professor
of Anesthesiology B.A.
in Organic Chemistry (1968) Ph.D.
in Biology (1973) |
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Many cells respond to extracellular molecules by means of chemically activated ion channels in their cell membrane. This process is extremely important in the nervous system, where transmitter-activated channels underlie synaptic transmission. The goal of work in my lab is to determine how transmitter-gated channels are activated, and how cells control the way in which their chemically activated channels function. This research involves biophysical techniques to measure membrane currents (voltage clamp and patch clamp recordings) and biochemical studies of receptor structure and pharmacology. The data are analysed to provide estimates of drug affinities and channel opening and closing rates. Much of the work is focused on nicotinic receptors, since we have a good understanding of receptor function in normal conditions. Both the muscle nicotinic receptors and some brain neuronal nicotinic receptors are studies. We also study a related channel, the GABA-A receptor, which is the receptor mediating fast inhibition in the central nervous system. A major goal of this work is to understand the structural and functional basis for the action of steroid and barbiturate anesthetics on this channel. We have been generating new cell lines expressing recombinant receptor proteins, to extend studies of the relationship between structure and function. We use wild type and mutated subunits, to examine the structural requirements for drug action. |
Li P, Covey DF, Steinbach JH, and Akk G (2006) Dual potentiating and inhibitory actions of a benz[e]indene neurosteroid analog on recombinant alpha1beta2gamma2 GABAA receptors. Molecular Pharmacology 69(6): 2015-2026. |
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Li W, Covey DF, Alakoskela JM, Kinnunen PKJ, and Steinbach JH (2006) Enantiomers of neuroactive steroids support a specific interaction with the GABA-C receptor as the mechanism of steroid action. Molecular Pharmacology 69(6): 1779-1782. |
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McCann CM, Bracamontes J., Steinbach JH, and Sanes JR (2006) the cholinergic antagonist alpha-bungarotoxin also binds and blocks a subset of GABA receptors. PNAS 103(13): 5149-5154. |
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Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, and Mennerick, S. (2005) Neurosteroid access to the GABAA receptor. J Neurosci 25(50): 11605-13. |
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Akk G, and Steinbach JH (2005) Galantamine activates muscle-type nicontinic acetylcholine receptors without binding to the acetylcholine-binding site. J Neurosci 25(8): 1992-2001. |
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Akk G, Bracamontes JR, Covey DF, Evers A, Dao T and Steinbach JH (2004) Neuroactive steroids have multiple actions to potentiate GABA(A) receptors. J Physiol 558(Pt 1): 59-74. |
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Akk G, Bracamontes JF and Steinbach JH (2004) Activation of GABA(A) receptors containing the alpha4 subunit by GABA and pentobarbital. J Physiol 556(Pt 2):387-99. |
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Darbandi-Tonkabon F, Manion BD, Hastings WR, Craigen WJ, Akk G, Bracamontes JF, He Y, Sheiko TV, Steinbach JH, Mennerick SJ, Covey DF and Evers AS (2004) Neuroactive steroid interactions with voltage-dependent anion channels: lack of relationship to GABA(A) receptor modulation and anesthesia. J Pharmacol Exp Ther 308(2): 502-11. |
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Paradiso KG and Steinbach JH (2003) Nicotine is highly effective at producing desensitization of rat alpha4beta2 neuronal nicotinic receptors. J Physiol 553(Pt 3): 857-71. |
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Akk G and Steinbach JH (2003) Activation and block of mouse muscle-type nicotinic receptors by tetraethylammonium. J Physiol 551(Pt 1): 155-68. |
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Akk G and Steinbach JH (2003) Low doses of ethanol and a neuroactive steroid positively interact to modulate rat GABA(A) receptor function. J Physiol 546(Pt3): 641-46. |
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Darbandi-Tonkabon F, Hastings WR, Zeng CM, Akk G, Manion BD, Bracamontes JF, Steinbach JH, Mennerick SJ, Covey DF and Evers AS (2003) Photoaffinity labeling with a neuroactive steroid analogue. 6-azippregnanolone labels voltage-dependent anion channel-1 in rat brain. J Biol Chem 278(15): 13196-206. |
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Zhang J and Steinbach JH (2003) Cytisine binds with similar affinity to nicotinic alpha4beta2 receptors on the cell surface and in homogenates. Brain Res. 959(1): 98-102. |
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Wang M, He Y, Eisenman LN, Fields C, Zeng CM, Mathews J, Benz A Fu T, Zorumski E, Steinbach JH, Covey DF, Zorumski CF and Mennerick S (2002) 3beta-hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists. J Neurosci 22(9): 3366-75. |
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Steinbach JH and Akk G (2001) Modulation of GABA(A) receptor channel gating by pentobarbital. J Physiol 537(Pt 3): 715-33. |
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Paradiso K, Zhang J and Steinbach JH (2001) The C-terminus of the human nicotinic alpha4beta2 receptor forms a binding site required for potentiation by an estrogenic steroid. J Neurosci. 21(17): 6561-68. |
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Akk G, Bracamontes J and Steinbach JH (2001) Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit. J Physiol 532(Pt 3): 673-84. |
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Akk G and Steinbach JH (2000) Structural elements near the C-terminus are responsible for changes in nicotinic receptor kinetics following patch excision. J Physiol 527(Pt3): 405-17. |
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Paradiso K, Sabey K, Evers AS, Zorumski CF, Covey DF and Steinbach JH (2000) Steroid inhibition of rat neuronal nicotinic alpha4beta2 receptors expressed in HEK 293 cells. Mol Pharmacol 58(2): 341-51. |
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Steinbach JH, Bracamontes J, Yu L, Zhang P and Covey DF (2000) Subunit-specific action of an anticonvulsant thiobuyrolactone on recombinanat glycine receptors involves a residue in the M2 membrane-spanning region. Mol Pharmacol 58(1): 11-17. |
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Akk G and Steinbach JH (2000) Activation and block of recombinant GABA(A) receptors by pentobarbitone: a single-channel study. Br J Pharmacol 130(2): 249-58. |
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| Serafini F, Bracamontes J and Steinbach JH (2000) Structural domains of the human GABA(A) receptor 3 subunit involved in the actions of pentobarbital. J Physiol 524(Pt 3): 649-76. |