Abstract
Ethanol (EtOH), the main ingredient in alcoholic beverages, is well known for its behavioral, physiological, and immunosuppressive effects. There is evidence that EtOH acts through protein targets to exert its physiological effects; however, the mechanisms underlying EtOH's effects on inflammatory processes, particularly at the blood-brain barrier (BBB), are still poorly understood. Transient receptor potential (TRP) channels, the vanguards of human sensory systems, are novel molecular receptors significantly affected by EtOH, and are heavily expressed in brain microvascular endothelial cells (BMVECs), one of the cellular constituents of the BBB. EtOH's actions on endothelial TRP channels could affect intracellular Ca2+ and Mg2+ dynamics, which mediate leukocyte adhesion to endothelial cells and endothelial permeability at the BBB, thus altering immune and inflammatory responses. We examined the basal expression profiles of all 29 known mammalian TRP channels in mouse BMVECs and determined both EtOH concentration- and time-dependent effects on TRP expression using a PCR array. We also generated an in vitro BBB model to examine the involvement of a chosen TRP channel, TRP melastatin 7 (TRPM7), in EtOH-mediated alteration of BBB permeability. With the exception of the akyrin subfamily, members of five TRP subfamilies were expressed in mouse BMVECs, and their expression levels were modulated by EtOH in a concentration-dependent manner. In the in vitro BBB model, TRPM7 antagonists further enhanced EtOH-mediated alteration of BBB permeability. Because of the diversity of TRP channels in BMVECs that regulate cellular processes, EtOH can affect Ca2+/Mg2+ signaling, immune responses, lysosomal functions as well as BBB integrity.