Additivity and independence of neuroprotective effects of GABAA and GABAB receptor agonists in complete global cerebral ischemia

Kulinskii, V. I.; Михельсон, Г. В.

doi:10.1007/bf02681942

Cited by 9 publications

(7 citation statements)

References 4 publications

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“…If such an effect was also manifest presynaptically, then we would predict that AMPK should also increase the inactivation of Ca 2+ channels via GABA B receptor activation, leading to decreased release of glutamate, GABA and a range of other neurotransmitters, which may have varying effects on neuronal survival. However, it is interesting to note that GABA B receptor agonists are neuroprotective in animal models of ischemia, further highlighting a predominant role for these receptors in limiting neuronal activity after ischemic/anoxic injury (Kulinskii and Mikhel'son, 2000); (Dave et al, 2005) (Jackson-Friedman et al, 1997. Finally, and in agreement with these whole animal studies, we were able to establish that phosphorylation of S783 appears to play a neuroprotective role in cultured neurons after anoxia.…”

Section: Modulation Of Ampk After Ischemic Insultsupporting

confidence: 80%

Phospho-Dependent Functional Modulation of GABAB Receptors by the Metabolic Sensor AMP-Dependent Protein Kinase

Kuramoto

Wilkins

Fairfax

et al. 2007

Neuron

166

163

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GABA(B) receptors are heterodimeric G protein-coupled receptors composed of R1 and R2 subunits that mediate slow synaptic inhibition in the brain by activating inwardly rectifying K(+) channels (GIRKs) and inhibiting Ca(2+) channels. We demonstrate here that GABA(B) receptors are intimately associated with 5'AMP-dependent protein kinase (AMPK). AMPK acts as a metabolic sensor that is potently activated by increases in 5'AMP concentration that are caused by enhanced metabolic activity, anoxia, or ischemia. AMPK binds the R1 subunit and directly phosphorylates S783 in the R2 subunit to enhance GABA(B) receptor activation of GIRKs. Phosphorylation of S783 is evident in many brain regions, and is increased dramatically after ischemic injury. Finally, we also reveal that S783 plays a critical role in enhancing neuronal survival after ischemia. Together our results provide evidence of a neuroprotective mechanism, which, under conditions of metabolic stress or after ischemia, increases GABA(B) receptor function to reduce excitotoxicity and thereby promotes neuronal survival.

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Section: Modulation Of Ampk After Ischemic Insultsupporting

confidence: 80%

Phospho-Dependent Functional Modulation of GABAB Receptors by the Metabolic Sensor AMP-Dependent Protein Kinase

Kuramoto

Wilkins

Fairfax

et al. 2007

Neuron

166

163

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“…These data suggest that agonist activation of GABA receptors can be mutually modulated by the association between these two different classes of GABA receptor. Additionally, Kulinskii and Mikhel'son [29] have found that GABA(B) receptors agonist baclofen and GABA(A) receptors agonists THIP and muscimol are additively contribute to the improvement of brain resistance to global ischemia. As to our findings in present study that coapplication of GABA(B) receptors and GABA(A) receptors agonists are more effective than solely used, our observations further suggest that these two receptor types may cooperate to produce inhibitory synaptic transmission.…”

Section: Discussionmentioning

confidence: 99%

Co‐activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6‐PSD95‐MLK3 signaling module in cerebral ischemic‐reperfusion

et al. 2008

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In this study, we investigated whether the increase of inhibitory c-amino butyric acid (GABA) signal suppresses the excitatory glutamate signal induced by cerebral ischemia and the underlying mechanisms. In global cerebral ischemia, focal cerebral ischemia and oxygen-glucose deprivation, application of muscimol and baclofen, agonists of GABA(A) receptor and GABA(B) receptor, exerted neuroprotection. The agonists inhibited the increased assembly of the GluR6-PSD-95-MLK3 module induced by cerebral ischemia and the activation of the MLK3-MKK4/7-JNK3 cascade. Our results suggest that stimulation of the inhibitory GABA receptors can attenuate the excitatory JNK3 apoptotic signaling pathway via inhibiting the increased assembly of the GluR6-PSD-95-MLK3 signaling module in cerebral ischemia.

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“…Utilizing a multiple ligand simultaneous docking (MLSD) model, a group has identified raloxifene and bazedoxifene as potent inhibitors of the IL-6/GP130 interface, a critical step in the STAT3-mediated pathway of cancer progression (152). In the context of cerebral ischemia and neuropathic pain, GABAB receptors are often excessively upregulated (153, 154), and small peptides interfering with GABA-interacting proteins such as 14–3–3 may selectively restore normal GABA function without affecting the GABA receptors not implicated in disease (155, 156). Disruption of metabotropic glutamate receptor (mGluR7a) interaction with proteins interacting with kinase 1 (PICK1) has been shown to induce the absence of seizures in rodents, suggesting that small molecules that stabilize this interaction could be potential therapeutics against epilepsy (157).…”

Section: Ais Targeting As a Pharmacological Strategymentioning

confidence: 99%

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

2014

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The progress of developing effective interventions against psychiatric disorders has been limited due to a lack of understanding of the underlying cellular and functional mechanisms. Recent research findings focused on exploring novel causes of psychiatric disorders have highlighted the importance of the axonal initial segment (AIS), a highly specialized neuronal structure critical for spike initiation of the action potential. In particular, the role of voltage-gated sodium channels, and their interactions with other protein partners in a tightly regulated macromolecular complex has been emphasized as a key component in the regulation of neuronal excitability. Deficits and excesses of excitability have been linked to the pathogenesis of brain disorders. Identification of the factors and regulatory pathways involved in proper AIS function, or its disruption, can lead to the development of novel interventions that target these mechanistic interactions, increasing treatment efficacy while reducing deleterious off-target effects for psychiatric disorders.

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Additivity and independence of neuroprotective effects of GABAA and GABAB receptor agonists in complete global cerebral ischemia

Cited by 9 publications

References 4 publications

Phospho-Dependent Functional Modulation of GABAB Receptors by the Metabolic Sensor AMP-Dependent Protein Kinase

Phospho-Dependent Functional Modulation of GABAB Receptors by the Metabolic Sensor AMP-Dependent Protein Kinase

Co‐activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6‐PSD95‐MLK3 signaling module in cerebral ischemic‐reperfusion

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

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