Distinct Deactivation and Desensitization Kinetics of Recombinant GABAA Receptors

Tia, Sutthichai; Wang, J. F.; Kotchabhakdi, Naiphinich; Vicini, Stefano

doi:10.1016/s0028-3908(96)00018-4

Cited by 109 publications

(101 citation statements)

References 16 publications

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“…1D). A similar speeding of sPSC decay was recently reported by Tia et al (1996) and was attributed, in part, to a change in the subunit composition of synaptic GABAA receptors. As is apparent from Fig.…”

Section: Resultssupporting

confidence: 85%

“…At most GABAergic synapses the release of transmitter usually results in the synchronous activation of ligand-gated ion channels, giving rise to fast events which operate in the millisecond time range. While granule cells exhibit such GABAA receptormediated postsynaptic currents (PSCs), recent experiments have identified an additional tonic conductance that appears to arise from persistent activation of these receptors (Kaneda, Farrant & Cull-Candy, 1995;Tia, Wang, Kotchabhakdi & Vicini, 1996;Wall & Usowicz, 1996). The functional significance of this tonic conductance is unknown.…”

mentioning

confidence: 99%

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Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.

Brickley

Cull-Candy

Farrant

1996

The Journal of Physiology

671

636

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I To investigate the origin and functional significance of a recently described tonic GABAA receptor-mediated conductance in cerebellar granule cells we have made recordings from cells in cerebellar slices from rats of different ages (postnatal days P4 to P28). 2. During development there was a dramatic change in the properties of GABA-mediated synaptic transmission. The contribution to GABAA receptor-mediated charge transfer from the tonic conductance (GGABA), relative to that resulting from discrete spontaneous postsynaptic currents (sPSCs), was increased from 5 % at P7 to 99 % at P21. GGABA was reduced by bicuculline, tetrodotoxin and by lowering extracellular Ca2+, and was initially present only in those cells which exhibited sPSCs. 3. At P7 sPSCs were depolarizing, occasionally triggering a single action potential. By P18 the GABA reversal potential was shifted close to the resting potential and GGABA produced a shunting inhibition. Removal of GGABA by bicuculline increased granule cell excitability in response to current injection. 4. This novel tonic inhibition is present despite the low number of Golgi cell synapses on individual granule cells and appears to result from 'overspill' of synaptically released GABA leading to activation of synaptic and extrasynaptic GABAA receptors.

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Section: Resultssupporting

confidence: 85%

mentioning

confidence: 99%

Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.

Brickley

Cull-Candy

Farrant

1996

The Journal of Physiology

671

636

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“…channel closing upon agonist deoccupancy. Deactivation rates measured are consistent with literature values for GABA A (36,43,44) and glutamate or nicotinic receptors (21,45,46). These deactivation rates are slow (50-100 ms) compared with the time required to remove GABA from the recording chamber (Ͻ10 ms), so the differences measured are highly significant.…”

Section: Discussionsupporting

confidence: 87%

The γ-aminobutyric acid type A (GABA _A ) receptor-associated protein (GABARAP) promotes GABA _A receptor clustering and modulates the channel kinetics

Chen

Wang

Vicini

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

193

169

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“…Application of a brief pulse of GABA (1 mM, 1-4 msec) elicited currents with kinetics that closely resemble GABA A receptormediated IPSCs (Jones and Westbrook, 1995;Tia et al, 1996). Similar to its effect on synaptic transmission, halothane (0.43 mM) significantly prolonged current deactivation (Fig.…”

Section: Resultsmentioning

confidence: 73%

Effects of Halothane on GABA_AReceptor Kinetics: Evidence for Slowed Agonist Unbinding

Li¹,

Pearce

2000

J. Neurosci.

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Many anesthetics, including the volatile agent halothane, prolong the decay of GABA A receptor-mediated IPSCs at central synapses. This effect is thought to be a major factor in the production of anesthesia. A variety of different kinetic mechanisms have been proposed for several intravenous agents, but for volatile agents the kinetic mechanisms underlying this change remain unknown. To address this question, we used rapid solution exchange techniques to apply GABA to recombinant GABA A receptors (␣ 1 ␤ 2 ␥ 2s ) expressed in HEK 293 cells, in the absence and presence of halothane. To differentiate between different microscopic kinetic steps that may be altered by the anesthetic, we studied a variety of measures, including peak concentration-response characteristics, macroscopic desensitization, recovery from desensitization, maximal current activation rates, and responses to the low-affinity agonist taurine. Experimentally observed alterations were compared with predictions based on a kinetic scheme that incorporated two agonist binding steps, and open and desensitized states. We found that, in addition to slowing deactivation after a brief pulse of GABA, halothane increased agonist sensitivity and slowed recovery from desensitization but did not alter macroscopic desensitization or maximal activation rate and only slightly slowed rapid deactivation after taurine application. This pattern of responses was found to be consistent with a reduction in the microscopic agonist unbinding rate (k off ) but not with changes in channel gating steps, such as the channel opening rate (␤), closing rate (␣), or microscopic desensitization. We conclude that halothane slows IPSC decay by slowing dissociation of agonist from the receptor. Key words: GABA; halothane; taurine; synaptic inhibition; anesthetics; receptor kineticsThe activity of ligand-gated ion channels can be described in kinetic terms by defining transition rates between individual metastable states of the receptor. Drug action can then be viewed as altering the transition rates between these states, under the assumption that drug binding does not introduce new transitions to the kinetic scheme. Using this approach to study pharmacological modulation of the GABA A receptor, it has been proposed that barbiturates alter transition rates between agonist-bound closed states (Macdonald et al., 1989a;Macdonald and Olsen, 1994), neurosteroids decrease the exit rate from the desensitized state of the receptor (Zhu and Vicini, 1997), and benzodiazepines increase the agonist binding rate (Rogers et al., 1994) or decrease agonist unbinding rate and accelerate desensitization (Mellor and Randall, 1997). In addition, it has been proposed that dephosphorylation of the GABA A receptor reduces the agonist unbinding rate, slowing deactivation and prolonging inhibitory currents (Jones and Westbrook, 1997).The volatile anesthetic halothane prolongs GABA A receptormediated IPSCs (Gage and Robertson, 1985;Mody et al., 1991;Jones and Harrison, 1993;Pearce, 1996), as do a great number o...

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Distinct Deactivation and Desensitization Kinetics of Recombinant GABAA Receptors

Cited by 109 publications

References 16 publications

Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.

Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.

The γ-aminobutyric acid type A (GABA _A ) receptor-associated protein (GABARAP) promotes GABA _A receptor clustering and modulates the channel kinetics

Effects of Halothane on GABA_AReceptor Kinetics: Evidence for Slowed Agonist Unbinding

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Distinct Deactivation and Desensitization Kinetics of Recombinant GABAA Receptors

Cited by 109 publications

References 16 publications

Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.

Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.

The γ-aminobutyric acid type A (GABA A ) receptor-associated protein (GABARAP) promotes GABA A receptor clustering and modulates the channel kinetics

Effects of Halothane on GABAAReceptor Kinetics: Evidence for Slowed Agonist Unbinding

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The γ-aminobutyric acid type A (GABA _A ) receptor-associated protein (GABARAP) promotes GABA _A receptor clustering and modulates the channel kinetics

Effects of Halothane on GABA_AReceptor Kinetics: Evidence for Slowed Agonist Unbinding