Inhibition of type a GABA receptors by L-type calcium channel blockers

Das, Paromita; Bell-Horner, Cathy L.; Huang, Ren-Qi; Raut, Atul; Gonzales, Eric B.; Chen, Z. L.; Covey, Douglas F.; Dillon, Glenn H.

doi:10.1016/j.neuroscience.2003.12.005

Cited by 39 publications

(30 citation statements)

References 38 publications

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“…The results from several other studies corroborate the finding that in addition to L-type calcium channels, dihydropyridines inhibit voltage-gated sodium channels, voltage-gated potassium channels, and GABA A receptors [90; 91; 92; 93]. Since progesterone and dihydrophyridines share neuroprotective [94; 95] and ion channel modulatory properties, they may share a similar mechanism of receptor binding and inhibition.…”

Section: Progesterone-dependent Modulation Of Additional Ion-channelssupporting

confidence: 77%

Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection

Luoma

Stern

Mermelstein

2012

The Journal of Steroid Biochemistry and Molecular Biology

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Progesterone is being utilized as a therapeutic means to ameliorate neuron loss and cognitive dysfunction following traumatic brain injury Although there have been numerous attempts to determine the means by which progesterone exerts neuroprotective effects, studies describing the underlying molecular mechanisms are lacking What has become clear, however, is the notion that progesterone can thwart several physiological processes that are detrimental to neuron function and survival, including inflammation, edema, demyelination and excitotoxicity One clue regarding the means by which progesterone has restorative value comes from the notion that these aforementioned biological processes all share the common theme of eliciting pronounced increases in intracellular calcium. Thus, we propose the hypothesis that progesterone regulation of calcium signaling underlies its ability to mitigate these cellular insults, ultimately leading to neuroprotection. Further, we describe recent findings that indicate neuroprotection is achieved via progesterone block of voltage-gated calcium channels, although additional outcomes may arise from blockade of various other ion channels and neurotransmitter receptors.

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Section: Progesterone-dependent Modulation Of Additional Ion-channelssupporting

confidence: 77%

Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection

Luoma

Stern

Mermelstein

2012

The Journal of Steroid Biochemistry and Molecular Biology

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“…Changes to α1 and α3 occurred in both sham and injured animals, indicating drug effects that overrode the injury effects. Some L-type channel blockers have known effects on receptors such as NMDA [63] or GABA-A [64], but diltiazem has been shown to have no direct effect on recombinant α1β2γ2 receptors [65]. However, VGCC regulation of GABA A R surface expression may be a common mechanism since it has been implicated after hypoxia [66] and extended GABA exposure [67].…”

Section: Discussionmentioning

confidence: 99%

Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus

2010

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BackgroundExcitatory amino acid release and subsequent biochemical cascades following traumatic brain injury (TBI) have been well documented, especially glutamate-related excitotoxicity. The effects of TBI on the essential functions of inhibitory GABA-A receptors, however, are poorly understood.MethodsWe used Western blot procedures to test whether in vivo TBI in rat altered the protein expression of hippocampal GABA-A receptor subunits α1, α2, α3, α5, β3, and γ2 at 3 h, 6 h, 24 h, and 7 days post-injuy. We then used pre-injury injections of MK-801 to block calcium influx through the NMDA receptor, diltiazem to block L-type voltage-gated calcium influx, or diazepam to enhance chloride conductance, and re-examined the protein expressions of α1, α2, α3, and γ2, all of which were altered by TBI in the first study and all of which are important constituents in benzodiazepine-sensitive GABA-A receptors.ResultsWestern blot analysis revealed no injury-induced alterations in protein expression for GABA-A receptor α2 or α5 subunits at any time point post-injury. Significant time-dependent changes in α1, α3, β3, and γ2 protein expression. The pattern of alterations to GABA-A subunits was nearly identical after diltiazem and diazepam treatment, and MK-801 normalized expression of all subunits 24 hours post-TBI.ConclusionsThese studies are the first to demonstrate that GABA-A receptor subunit expression is altered by TBI in vivo, and these alterations may be driven by calcium-mediated cascades in hippocampal neurons. Changes in GABA-A receptors in the hippocampus after TBI may have far-reaching consequences considering their essential importance in maintaining inhibitory balance and their extensive impact on neuronal function.

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“…Das et al evaluated the ability of some 1,4-DHPs to regulate recombinant GABA-A receptors of known subunit configuration, and used a pharmacologic approach and site-directed-mutagenesis to determine whether the effects of 1,4-DHPs are due to their interaction at known GABA-A receptor modulatory sites [163]. It was observed that nifedipine and nitrendipine (Fig.…”

Section: Inhibitors Of Gaba a Receptorsmentioning

confidence: 99%

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

Ioan¹,

Carosati²,

Micucci³

et al. 2011

CMC

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Since the pioneering studies of Fleckenstein and co-workers, L-Type Calcium Channel (LTCC) blockers have attracted large interest due to their effectiveness in treating several cardiovascular diseases. Medicinal chemists achieved high potency and tissue selectivity by decorating the 1-4-DHP nucleus, the most studied scaffold among LTCC blockers. Nowadays it is clear that the 1,4-DHP nucleus is a privileged scaffold since, when appropriately substituted, it can selectively modulate diverse receptors, channels and enzymes. Therefore, the 1,4-DHP scaffold could be used to treat various diseases by a single-ligand multi-target approach. In this review, we describe the structure-activity relationships of 1,4-DHPs at ion channels, G-protein coupled receptors, and outline the potential for future therapeutic applications.

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Inhibition of type a GABA receptors by L-type calcium channel blockers

Cited by 39 publications

References 38 publications

Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection

Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection

Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus

1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

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