Homer2 and Alcohol: A Mutual Interaction

Abstract

The past two decades of data derived from addicted individuals and preclinical animal models of addiction implicate a role for the excitatory glutamatergic transmission within the mesolimbic structures in alcoholism. The cellular localization of the glutamatergic receptor subtypes, as well as their signaling efficiency and function, are highly dependent upon discrete functional constituents of the postsynaptic density, including the Homer family of scaffolding proteins. The consequences of repeated alcohol administration on the expression of the Homer family proteins demonstrate a crucial and active role, particularly for the expression of Homer2 isoform, in regulating alcohol-induced behavioral and cellular neuroplasticity. The interaction between Homer2 and alcohol can be defined as a mutual relation: alcohol consumption enhances the expression of Homer2 protein isoform within the nucleus accumbens and the extended amygdala, cerebral areas where, in turn, Homer2 is able to mediate the development of the "pro-alcoholic" behavioral phenotype, as a consequence of the morpho-functional synaptic adaptations. Such findings are relevant for the detection of the strategic molecular components that prompt alcohol-induced functional and behavioral disarrangement as targets for future innovative treatment options.

Keywords: Homer proteins; Homer2; addiction; alcohol; glutamate.

Figure 1

Homer proteins form a physical link among signaling molecules in glutamatergic postsynaptic density (PSD). Long Homer forms (Homer1b/c; Homer2a/b; Homer3a/b) bind to each other through their carboxy-terminal domains and to the target proteins: Group1 of metabotropic glutamate receptors (mGluRs); Ca²⁺-signaling-related proteins, including phospholipase C-ß (PLCß), inositol 1,4,5-trisphosphate receptors (IP₃-R), ryanodine receptors (Ry-R), transient receptor potential canonical ion channels [voltage-dependent Ca2⁺ channel (VDCC)]; PSD scaffolding proteins, such as Shank component of the NMDA receptor-associated PSD-95 complex. The binding to these molecules allows Homers to serve as a postsynaptic scaffold that crosslinks and, thus, regulates the functionality of the ligands. Long Homer isoforms additionally encode a C-terminal coiled-coil domain, which allows their multimerization at a specific site or subcellular compartment, such as the actin cytoskeleton. Synaptic multimerization of long Homer proteins probably regulates or facilitates signal transduction or cross-talk between target proteins. The short Homer isoform (Homer1a) lacks the coiled-coil domain and, therefore, cannot form multimers and functionally compete with the long Homer isoforms in binding postsynaptic signaling proteins. In this way, Homer1a acts as a natural dominant-negative regulator of the long Homers, causing rapid disruption of long Homer clusters and, consequently, affecting synaptic architecture.