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Waking action of ursodeoxycholic acid (UDCA) involves histamine and GABAA receptor block.

Yanovsky Y, Schubring SR, Yao Q, Zhao Y, Li S, May A, Haas HL, Lin JS, Sergeeva OA - PLoS ONE (2012)

Bottom Line: In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine.The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA.In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany.

ABSTRACT
Since ancient times ursodeoxycholic acid (UDCA), a constituent of bile, is used against gallstone formation and cholestasis. A neuroprotective action of UDCA was demonstrated recently in models of Alzheimer's disease and retinal degeneration. The mechanisms of UDCA action in the nervous system are poorly understood. We show now that UDCA promotes wakefulness during the active period of the day, lacking this activity in histamine-deficient mice. In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine. In histaminergic neurons recorded in slices UDCA reduced amplitude and duration of spontaneous and evoked IPSCs. In acutely isolated histaminergic neurons UDCA inhibited GABA-evoked currents and sIPSCs starting at 10 µM (IC(50) = 70 µM) and did not affect NMDA- and AMPA-receptor mediated currents at 100 µM. Recombinant GABA(A) receptors composed of α1, β1-3 and γ2L subunits expressed in HEK293 cells displayed a sensitivity to UDCA similar to that of native GABA(A) receptors. The mutation α1V256S, known to reduce the inhibitory action of pregnenolone sulphate, reduced the potency of UDCA. The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.

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Recombinant α1β3γ2L GABAARs are blocked by UDCA in a way comparable to native receptors.A. UDCA and picrotoxin (PTX) induce outward shift in baseline current in HEK293 cells transfected with β-plasmid (block of constitutively open channels). Plot below shows averaged amplitudes of UDCA- and PTX- responses (4–10 cells for each concentration). Note lack of additivity between maximal UDCA and PTX induced outward currents. B. Histamine (HA)-evoked inward currents and their reversible blockade by different concentrations of UDCA at homopentameric GABAA receptors. C. Concentration-response curves for UDCA-block of control (co) either GABA (0.5 mM)- or histamine (HA, 5 mM)- evoked currents obtained from 4 different receptor types fitted with the following IC50s(nH): α1β3γ2L: 73±16 µM (0.63); α1β: 81±16 µM (0.65); β3γ2L: 232±66 µM (0.62); β3: 7.4±2 µM (0.8). Four to ten cells were investigated with the whole concentration range for each receptor type. D. Examples of current recordings in α1β3-expressing HEK293 cell: GABA (dotted line)- or GABA+UDCA – responses are superimposed.
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pone-0042512-g006: Recombinant α1β3γ2L GABAARs are blocked by UDCA in a way comparable to native receptors.A. UDCA and picrotoxin (PTX) induce outward shift in baseline current in HEK293 cells transfected with β-plasmid (block of constitutively open channels). Plot below shows averaged amplitudes of UDCA- and PTX- responses (4–10 cells for each concentration). Note lack of additivity between maximal UDCA and PTX induced outward currents. B. Histamine (HA)-evoked inward currents and their reversible blockade by different concentrations of UDCA at homopentameric GABAA receptors. C. Concentration-response curves for UDCA-block of control (co) either GABA (0.5 mM)- or histamine (HA, 5 mM)- evoked currents obtained from 4 different receptor types fitted with the following IC50s(nH): α1β3γ2L: 73±16 µM (0.63); α1β: 81±16 µM (0.65); β3γ2L: 232±66 µM (0.62); β3: 7.4±2 µM (0.8). Four to ten cells were investigated with the whole concentration range for each receptor type. D. Examples of current recordings in α1β3-expressing HEK293 cell: GABA (dotted line)- or GABA+UDCA – responses are superimposed.

Mentions: Among the 19 known GABAAR subunits only a restricted number forms functional combinations in the brain [24]. Our aims were: i) to compare the effects of BS on native and recombinant GABAAR of similar subunit composition as seen in hypothalamic neurons (express α1, α2, β1, β3, γ1 and γ2 subunits [23], [25]); ii) to find the minimal structural requirements for the UDCA inhibition. Coapplication of UDCA with 1 mM GABA inhibited the peak current and increased the apparent desensitization rate in cells expressing α1β3 and α1β3γ2L GABAARs (Fig. 6). The concentrations producing half-maximal effects on steady-state currents (81 µM for α1β3 and 73 µM for α1β3γ2L) were similar to those measured on native receptors (92 µM, Table S1). Changing the subtype of the β subunit had no significant effect on the ability of UDCA to inhibit the currents. The IC50 for UDCA was 96±17 µM and 85±11 µM in α1β1γ2L and α1β2γ2L receptors, respectively.


Waking action of ursodeoxycholic acid (UDCA) involves histamine and GABAA receptor block.

Yanovsky Y, Schubring SR, Yao Q, Zhao Y, Li S, May A, Haas HL, Lin JS, Sergeeva OA - PLoS ONE (2012)

Recombinant α1β3γ2L GABAARs are blocked by UDCA in a way comparable to native receptors.A. UDCA and picrotoxin (PTX) induce outward shift in baseline current in HEK293 cells transfected with β-plasmid (block of constitutively open channels). Plot below shows averaged amplitudes of UDCA- and PTX- responses (4–10 cells for each concentration). Note lack of additivity between maximal UDCA and PTX induced outward currents. B. Histamine (HA)-evoked inward currents and their reversible blockade by different concentrations of UDCA at homopentameric GABAA receptors. C. Concentration-response curves for UDCA-block of control (co) either GABA (0.5 mM)- or histamine (HA, 5 mM)- evoked currents obtained from 4 different receptor types fitted with the following IC50s(nH): α1β3γ2L: 73±16 µM (0.63); α1β: 81±16 µM (0.65); β3γ2L: 232±66 µM (0.62); β3: 7.4±2 µM (0.8). Four to ten cells were investigated with the whole concentration range for each receptor type. D. Examples of current recordings in α1β3-expressing HEK293 cell: GABA (dotted line)- or GABA+UDCA – responses are superimposed.
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Related In: Results  -  Collection

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pone-0042512-g006: Recombinant α1β3γ2L GABAARs are blocked by UDCA in a way comparable to native receptors.A. UDCA and picrotoxin (PTX) induce outward shift in baseline current in HEK293 cells transfected with β-plasmid (block of constitutively open channels). Plot below shows averaged amplitudes of UDCA- and PTX- responses (4–10 cells for each concentration). Note lack of additivity between maximal UDCA and PTX induced outward currents. B. Histamine (HA)-evoked inward currents and their reversible blockade by different concentrations of UDCA at homopentameric GABAA receptors. C. Concentration-response curves for UDCA-block of control (co) either GABA (0.5 mM)- or histamine (HA, 5 mM)- evoked currents obtained from 4 different receptor types fitted with the following IC50s(nH): α1β3γ2L: 73±16 µM (0.63); α1β: 81±16 µM (0.65); β3γ2L: 232±66 µM (0.62); β3: 7.4±2 µM (0.8). Four to ten cells were investigated with the whole concentration range for each receptor type. D. Examples of current recordings in α1β3-expressing HEK293 cell: GABA (dotted line)- or GABA+UDCA – responses are superimposed.
Mentions: Among the 19 known GABAAR subunits only a restricted number forms functional combinations in the brain [24]. Our aims were: i) to compare the effects of BS on native and recombinant GABAAR of similar subunit composition as seen in hypothalamic neurons (express α1, α2, β1, β3, γ1 and γ2 subunits [23], [25]); ii) to find the minimal structural requirements for the UDCA inhibition. Coapplication of UDCA with 1 mM GABA inhibited the peak current and increased the apparent desensitization rate in cells expressing α1β3 and α1β3γ2L GABAARs (Fig. 6). The concentrations producing half-maximal effects on steady-state currents (81 µM for α1β3 and 73 µM for α1β3γ2L) were similar to those measured on native receptors (92 µM, Table S1). Changing the subtype of the β subunit had no significant effect on the ability of UDCA to inhibit the currents. The IC50 for UDCA was 96±17 µM and 85±11 µM in α1β1γ2L and α1β2γ2L receptors, respectively.

Bottom Line: In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine.The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA.In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany.

ABSTRACT
Since ancient times ursodeoxycholic acid (UDCA), a constituent of bile, is used against gallstone formation and cholestasis. A neuroprotective action of UDCA was demonstrated recently in models of Alzheimer's disease and retinal degeneration. The mechanisms of UDCA action in the nervous system are poorly understood. We show now that UDCA promotes wakefulness during the active period of the day, lacking this activity in histamine-deficient mice. In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(A)R antagonist gabazine. In histaminergic neurons recorded in slices UDCA reduced amplitude and duration of spontaneous and evoked IPSCs. In acutely isolated histaminergic neurons UDCA inhibited GABA-evoked currents and sIPSCs starting at 10 µM (IC(50) = 70 µM) and did not affect NMDA- and AMPA-receptor mediated currents at 100 µM. Recombinant GABA(A) receptors composed of α1, β1-3 and γ2L subunits expressed in HEK293 cells displayed a sensitivity to UDCA similar to that of native GABA(A) receptors. The mutation α1V256S, known to reduce the inhibitory action of pregnenolone sulphate, reduced the potency of UDCA. The mutation α1Q241L, which abolishes GABA(A)R potentiation by several neurosteroids, had no effect on GABA(A)R inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A) receptors.

Show MeSH
Related in: MedlinePlus