Receptors and Channels Associated with Alcohol Use: Contributions from Drosophila

Abstract

Alcohol Use Disorder (AUD) is a debilitating disorder that manifests as problematic patterns of alcohol use. At the core of AUD's behavioral manifestations are the profound structural, physiological, cellular, and molecular effects of alcohol on the brain. While the field has made considerable progress in understanding the neuromolecular targets of alcohol we still lack a comprehensive understanding of alcohol's actions and effective treatment strategies. Drosophila melanogaster is a powerful model for investigating the neuromolecular targets of alcohol because flies model many of the core behavioral elements of AUD and offer a rich genetic toolkit to precisely reveal the in vivo molecular actions of alcohol. In this review, we focus on receptors and channels that are often targeted by alcohol within the brain. We discuss the general roles of these proteins, their role in alcohol-associated behaviors across species, and propose ways in which Drosophila models can help advance the field.

Keywords: AUD; Alcohol; Drosophila; channels; receptors.

Figure 1.

Alcohol-related receptors, channels, and their downstream pathways. (a) GABA receptors are classified as either ionotropic (GABA_A/C) or metabotropic (GABA_B). GABA_A/C receptors are gated chloride-conducting ion channels whereas GABA_B receptors activate G_i/o proteins which inhibit adenylyl cyclase and decrease cAMP. (b) Glutamate receptors are classified as either ionotropic (AMPA, Kainate, and NMDA) or metabotropic (mGluRs) receptors. AMPA, Kainate, and NMDA receptors are all gated sodium-conducting cation channels, however, NMDA receptors also conduct calcium. mGluR are classified as groups I and II. Group I mGluRs activate G_q proteins which activate the PLC signaling pathway, whereas group II mGluRs activate G_i/o proteins which inhibit adenylyl cyclase and decrease cAMP. (c) Dopamine receptors are classified as D1- or D2-family members, which are both metabotropic receptors. However, D1 receptors activate G_s proteins thereby increasing cAMP, whereas D2 receptors activate G_i proteins thereby decreasing cAMP. (d) 5-HT receptors are classified as either ionotropic (5-HT3) or metabotropic (5HT1, 5-HT4,6,7, and 5-HT2) cation-permeable channel. 5-HT3 receptors are gated sodium-conducting cation channels. 5-HT3 receptors are not present in Drosophila. 5-HT metabotropic receptors activate either G_s, G_i, or G_q proteins to influence adenylyl cyclase and PLC signaling. (e) Calcium channels are gated by voltage. (f) Potassium channels are a diverse family that can be activated by Ca²⁺, voltage, the G βγ protein complex, and Na⁺. SLO2 is the fly homolog of the Na⁺ activated potassium channel, however it is not Na⁺ activated. Potassium channels also include two-pore domain K⁺ channels.

Figure 2.

General tools available for investigating alcohol-associated receptors, channels, and other proteins.