Activation of cyclic GMP-dependent protein kinase blocks alcohol-mediated cell death and calcium disruption in cerebellar granule neurons Journal Article

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Authors: Kouzoukas, D. E.; Bhalla, R. C.; Pantazis, N. J.
Article Title: Activation of cyclic GMP-dependent protein kinase blocks alcohol-mediated cell death and calcium disruption in cerebellar granule neurons
Abstract: Alcohol during brain development leads to the widespread neuronal death observed in fetal alcohol spectrum disorders (FASD). In comparison, the mature brain is less vulnerable to alcohol. Studies into maturation-acquired alcohol resistance uncovered a protective mechanism that reduces alcohol-induced neuronal death through nitric oxide-cGMP-cyclic GMP-dependent protein kinase (NO-cGMP-cGK) signaling. However, the downstream processes underlying this neuroprotection remain unclear. Alcohol can disrupt levels of intracellular calcium ([Ca(2+)]i) in vulnerable neuronal populations to trigger cell death in both in vivo and in vitro models of FASD. Since cGK has been demonstrated to regulate and inhibit intracellular Ca(2+) release, we examined the hypothesis that cGK confers alcohol resistance by preventing [Ca(2+)]i disruptions. Alcohol resistance, determined by neuronal survival after 24h of alcohol exposure, was examined in primary cerebellar granule neuron (CGN) cultures derived from 5 to 7day-old neonatal mice with an activator, 8-Br-cGMP, and/or an inhibitor, Rp-8-pCPT-cGMPS, of cGK signaling. Intracellular Ca(2+) responses to alcohol were measured by ratiometric Ca(2+) imaging in Fura-2-loaded CGN cultures after 8-Br-cGMP treatment. Our results indicate that activating cGK with 8-Br-cGMP before alcohol administration provided neuroprotection, which the cGK inhibitor, Rp-8-pCPT-cGMPS, blocked. Alcohol exposure elevated [Ca(2+)]i, whereas 8-Br-cGMP pretreatment reduced both the level of the alcohol-induced rise in [Ca(2+)]i as well as the number of cells that responded to alcohol by increasing [Ca(2+)]i. These findings associate alcohol resistance, mediated by cGK signaling, to reduction of the persistent and toxic increase in [Ca(2+)]i from alcohol exposure.
Journal Title: Neuroscience letters
Volume: 676
ISSN: 1872-7972; 0304-3940
Publisher: Elsevier Inc  
Journal Place: Ireland
Date Published: 2018
Start Page: 108
End Page: 112
Language: eng
DOI/URL:

S0304-3940(18)30289-1
Notes: LR: 20180424; CI: Copyright (c) 2018; GR: R01 AA011577/AA/NIAAA NIH HHS/United States; JID: 7600130; OTO: NOTNLM; 2018/02/23 00:00 [received]; 2018/04/09 00:00 [revised]; 2018/04/16 00:00 [accepted]; 2018/04/22 06:00 [pubmed]; 2018/04/22 06:00 [medline]; 2018/04/22 06:00 [entrez]; aheadofprint