Another noteworthy signal in the EA sample was observed in AKAP9, which produced 13 SNPs with p<10-4 and an empirical p=0.0005. Encoding a cytoskeletal protein, AKAP9 belongs to a family of structurally diverse A-kinase anchor proteins which regulate intracellular signaling through scaffolding and trafficking. The protein has been shown to co-localize with N-methyl-D-aspartate subunit 1 (GRIN1) (Lin et al. 1998) and through binding to the C-terminal of the NR1 receptor unit, it may be involved in the cytoskeletal anchoring of NMDA receptors, thereby serving a role in synaptic function (Lin et al. 1998). Anchor proteins at synaptic junctions facilitate specific clustering and anchoring of neurotransmitters and ion channels; evidence suggests that they can regulate signaling activity of NMDA receptors by modulating phosphorylation through interactions with phosphatase-kinase complexes (Dohrman et al. 2002; Westphal et al. 1999). In AD, NMDA receptors play a critical role by affecting tolerance, craving, withdrawal, and relapse (Kumari and Ticku 2000); alcohol may disrupt specificity of the signaling cascades and the protein-protein complexes (Ron 2004). Thus, by affecting the NMDA signaling cascade, AKAP9 would be involved in the molecular mechanisms of alcohol use disorders.
