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J Physiol
2009 Mar 01;587Pt 5:981-97. doi: 10.1113/jphysiol.2008.159343.
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Kinetic analysis of voltage-dependent potentiation and block of the glycine alpha 3 receptor by a neuroactive steroid analogue.
Jin X, Covey DF, Steinbach JH.
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We examined the actions of a carboxylated analogue of pregnanolone ((3alpha,5beta)-20-oxopregnane-3-carboxylic acid; 3alphaCOOH5betaP) on receptors composed of glycine receptor alpha3 subunits, expressed in Xenopus oocytes. This analogue both inhibits and potentiates this receptor; potentiation increases with more negative membrane potentials while block increases with less negative membrane potentials. We used a second analogue ((3alpha,5beta)-3-hydroxymethylpregnan-20-one; 3alphaCH(2)OH5betaP) to examine the mechanism for voltage-dependent potentiation. This analogue potentiates but does not block the glycine alpha3 receptor. Steady-state responses and current relaxations following voltage jumps support the idea that the voltage dependence of potentiation indirectly arises from a voltage dependence for channel activation by glycine, rather than an intrinsic voltage dependence for potentiation. Potentiation results from a slowing of the channel deactivation rate. In the absence of steroid, at a low [glycine] current relaxations after a voltage jump show two exponential components, with a weighted average time constant of approximately 425 ms (-50 mV, 22 degrees C). The rate for channel deactivation increases at more negative potentials (e-fold per 170 mV) whereas activation decreases (e-fold per 230 mV). The probability a channel is active at a high [glycine] is greater than 0.9. The addition of 10 microM 3alphaCH(2)OH5betaP decreases the deactivation rate by 6.3-fold (-50 mV). Voltage-dependent block by 3alphaCOOH5betaP is consistent with simple open-channel block, with voltage dependence reflecting interactions of the charge on the analogue with the electrical field. Block and unblock have equal but opposite dependence on membrane potential, and the charge on 3alphaCOOH5betaP senses approximately 70% of the membrane field at the blocking site. The apparent forward rate for block, however, is very slow (2 x 10(5) m(-1) s(-1)).
Adams,
Voltage jump analysis of procaine action at frog end-plate.
1977, Pubmed
Adams,
Voltage jump analysis of procaine action at frog end-plate.
1977,
Pubmed Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008,
Pubmed Akk,
Neuroactive steroids have multiple actions to potentiate GABAA receptors.
2004,
Pubmed Akk,
Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit.
2001,
Pubmed Akk,
Mechanisms of neurosteroid interactions with GABA(A) receptors.
2007,
Pubmed Belelli,
The interaction of general anaesthetics and neurosteroids with GABA(A) and glycine receptors.
1999,
Pubmed
,
Xenbase Betz,
Glycine receptors: recent insights into their structural organization and functional diversity.
2006,
Pubmed Bormann,
Mechanism of anion permeation through channels gated by glycine and gamma-aminobutyric acid in mouse cultured spinal neurones.
1987,
Pubmed Breitinger,
Hydroxylated residues influence desensitization behaviour of recombinant alpha3 glycine receptor channels.
2002,
Pubmed Burzomato,
Single-channel behavior of heteromeric alpha1beta glycine receptors: an attempt to detect a conformational change before the channel opens.
2004,
Pubmed Colquhoun,
Relaxation and fluctuations of membrane currents that flow through drug-operated channels.
1977,
Pubmed Colquhoun,
The actions of tubocurarine at the frog neuromuscular junction.
1979,
Pubmed Eisenman,
Activation-dependent properties of pregnenolone sulfate inhibition of GABAA receptor-mediated current.
2003,
Pubmed
,
Xenbase Gill,
Functional properties of spontaneous IPSCs and glycine receptors in rod amacrine (AII) cells in the rat retina.
2006,
Pubmed Grewer,
Investigation of the alpha(1)-glycine receptor channel-opening kinetics in the submillisecond time domain.
1999,
Pubmed Harvey,
GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.
2004,
Pubmed Heindl,
Kinetics and functional characterization of the glycine receptor alpha2 and alpha3 subunit.
2007,
Pubmed Herd,
Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors.
2007,
Pubmed Hosie,
Neurosteroid binding sites on GABA(A) receptors.
2007,
Pubmed Kuhse,
Identification and functional expression of a novel ligand binding subunit of the inhibitory glycine receptor.
1990,
Pubmed
,
Xenbase Legendre,
Voltage dependence of the glycine receptor-channel kinetics in the zebrafish hindbrain.
1999,
Pubmed Lewis,
Kinetic determinants of agonist action at the recombinant human glycine receptor.
2003,
Pubmed Li,
Neuroactive steroids and human recombinant rho1 GABAC receptors.
2007,
Pubmed
,
Xenbase Lynch,
Molecular structure and function of the glycine receptor chloride channel.
2004,
Pubmed Lynch,
Native glycine receptor subtypes and their physiological roles.
2009,
Pubmed Maksay,
Subunit-specific modulation of glycine receptors by neurosteroids.
2001,
Pubmed
,
Xenbase Mangin,
Kinetic properties of the alpha2 homo-oligomeric glycine receptor impairs a proper synaptic functioning.
2003,
Pubmed Meinck,
Startle and its disorders.
2006,
Pubmed Mennerick,
Effects on gamma-aminobutyric acid (GABA)(A) receptors of a neuroactive steroid that negatively modulates glutamate neurotransmission and augments GABA neurotransmission.
2001,
Pubmed
,
Xenbase Neher,
Voltage-dependence of drug-induced conductance in frog neuromuscular junction.
1975,
Pubmed Nikolic,
The human glycine receptor subunit alpha3. Glra3 gene structure, chromosomal localization, and functional characterization of alternative transcripts.
1998,
Pubmed Poisbeau,
Inflammatory pain upregulates spinal inhibition via endogenous neurosteroid production.
2005,
Pubmed Schofield,
The role of glycine and glycine receptors in myoclonus and startle syndromes.
2002,
Pubmed Sheridan,
Relaxation measurements on the acetylcholine receptor.
1975,
Pubmed Shu,
Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions.
2007,
Pubmed
,
Xenbase Smith,
Characterisation of inhibitory and excitatory postsynaptic currents of the rat medial superior olive.
2000,
Pubmed Steinbach,
Subunit-specific action of an anticonvulsant thiobutyrolactone on recombinant glycine receptors involves a residue in the M2 membrane-spanning region.
2000,
Pubmed
,
Xenbase Webb,
Molecular pharmacology of the glycine receptor chloride channel.
2007,
Pubmed Weir,
The interaction of anaesthetic steroids with recombinant glycine and GABAA receptors.
2004,
Pubmed
,
Xenbase Woodhull,
Ionic blockage of sodium channels in nerve.
1973,
Pubmed Wu,
Competitive inhibition of the glycine-induced current by pregnenolone sulfate in cultured chick spinal cord neurons.
1997,
Pubmed
