Potentiation of the GABAAR reveals variable energetic contributions by etiocholanolone and propofol

Pierce, Spencer R.; Xu, Sophia Q.; Germann, Allison L.; Steinbach, Joe Henry; Akk, Gustav

doi:10.1016/j.bpj.2023.09.014

Cited by 3 publications

(1 citation statement)

References 40 publications

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“…As discussed above, GABA binding to both agonist sites confer approximately -4.5 kcal/mol to channel gating as compared to -0.4 kcal/mol for DZ in the ECD site (Nors et al, 2021). Furthermore, the observed effect of DZ decreases with increasing baseline activity, similar to recent observations for the energetic effect of the anesthestic propofol and neurosteroid etiocholanolone on the closed/open equilibrium (Pierce et al, 2023). Indeed, functional studies show that DZ fails to potentiate responses to saturating GABA (Lavoie & Twyman, 1996; Perrais & Ropert, 1999; Rogers et al, 1994; Twyman et al, 1989; Vicini et al, 1987), suggesting that the presence of GABA may occlude the conformational effects of DZ in these structures.…”

Section: Discussionsupporting

confidence: 88%

Asymmetric roles for M2-M3 linkers of specific GABA_Areceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam

Nors,

Endres,

Goldschen-Ohm

2023

Preprint

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GABAAreceptors (GABAARs) are neurotransmitter-gated ion channels critical for inhibitory synaptic transmission as well as the molecular target for benzodiazepines (BZDs), one of the most widely prescribed class of psychotropic drugs today. Despite structural insight into the conformations underlying functional channel states, the detailed molecular interactions involved in conformational transitions and the physical basis for their modulation by BZDs are not fully understood. We previously identified that alanine substitution at the central residue in the α1 subunit M2-M3 linker (V279A) enhances the efficiency of linkage between the BZD site and the pore gate. Here, we expand on this work by investigating the effect of alanine substitutions at the analogous positions in the M2-M3 linkers of β2 (I275A) and γ2 (V290A) subunits, which together with α1 comprise typical heteromeric α1β2γ2 synaptic GABAARs. We find that these mutations confer subunit-specific effects on the intrinsic pore closed-open equilibrium and its modulation by the BZD diazepam (DZ). The mutations α1(V279A) or γ2(V290A) bias the channel toward a closed conformation, whereas β2(I275A) biases the channel toward an open conformation to the extent that the channel becomes leaky and opens spontaneously in the absence of agonist (e.g., GABA). In contrast, only α1(V279A) enhances the efficiency of DZ-to-pore linkage, whereas mutations in the other two subunits have no effect. These observations show that the central residue in the M2-M3 linkers of distinct subunits in synaptic α1β2γ2 GABAARs contribute asymmetrically to the intrinsic closed-open equilibrium and its modulation by DZ.

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Section: Discussionsupporting

confidence: 88%

Asymmetric roles for M2-M3 linkers of specific GABA_Areceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam

Nors,

Endres,

Goldschen-Ohm

2023

Preprint

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State-dependent energetics of GABAA receptor modulators

Borghese,

Goldschen-Ohm

2024

Biophysical Journal

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GABAA receptor subunit M2-M3 linkers have asymmetric roles in pore gating and diazepam modulation

Nors,

Endres,

Goldschen-Ohm

2024

Biophysical Journal

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Potentiation of the GABAAR reveals variable energetic contributions by etiocholanolone and propofol

Cited by 3 publications

References 40 publications

Asymmetric roles for M2-M3 linkers of specific GABA_Areceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam

Asymmetric roles for M2-M3 linkers of specific GABA_Areceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam

State-dependent energetics of GABAA receptor modulators

GABAA receptor subunit M2-M3 linkers have asymmetric roles in pore gating and diazepam modulation

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Potentiation of the GABAAR reveals variable energetic contributions by etiocholanolone and propofol

Cited by 3 publications

References 40 publications

Asymmetric roles for M2-M3 linkers of specific GABAAreceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam

Asymmetric roles for M2-M3 linkers of specific GABAAreceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam

State-dependent energetics of GABAA receptor modulators

GABAA receptor subunit M2-M3 linkers have asymmetric roles in pore gating and diazepam modulation

Contact Info

Product

Resources

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Asymmetric roles for M2-M3 linkers of specific GABA_Areceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam

Asymmetric roles for M2-M3 linkers of specific GABA_Areceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam