3a). Acute ethanol exposure has been shown to inhibit Ca2+ currents induced by PKC-dependent phosphorylation of mGluR5 in neurons42. Early studies in PC12 cell cultures also showed that ethanol has a significant inhibitory effect on the influx of Ca2+ through L-type voltage-gated Ca2+ channels43. Alcohol exposure also modulates Ca2+ signaling between astrocytes and neurons44 (Warden et al.), and Ca2+ acts as a second messenger that controls multiple processes in immune cells, including chemotaxis and secretion of pro- and anti-inflammatory cytokines. Our analyses provide further evidence that alcohol exposure alters Ca2+ signaling in the brains of alcoholics and could potentially alter communication between neurons and brain immune cells. Another module that correlated with alcohol dependence, brown4, was also enriched in immune response and infectious diseases, providing additional evidence for the role of the neuroimmune system in the etiology of alcohol dependence. Some of the differentially expressed genes in this network were also statistical significant in the gene-based tests (RASD1, UKBB-AC, P = 1.64 × 10−5 and ARID5A, UKBB-AC, P 1.4 × 10−3). The differentially expressed FKBP5 gene was also part of the brown module, but it was not identified as hub gene according to intra-modular connectivity (supplementary table 2).
