Figure 7.

Modulation of brain cell hemichannels by prenatal nicotine and postnatal high-fat/cholesterol diet. Prenatal nicotine and postnatal high-fat/cholesterol diet increase serum levels of IL-1β, leading to iNOS/COX₂ activation in microglia (1) and likely in astrocytes and neurons (not depicted). Possibly, PGE₂ released from microglia binds its EP₁ metabotropic receptors and produces the release of Ca²⁺ from intracellular stores (2). The increases in [Ca²⁺]_i is a known condition that evokes opening of Panx1 channels (Panx1 CHs), allowing the release of glutamate and ATP through them (3). ATP released via Panx1 CHs activates P2X₇ receptors (4), triggering a self-perpetuating mechanism, in which high levels of [Ca²⁺]_i could reactivate Panx1 CHs in microglia. In addition, paracrine release of glutamate and ATP from microglia could act on neighboring or distant neurons, resulting in the activation of P2X₇ (5) and NMDA (6) receptors, respectively. The latter enhances the activity of neuronal Panx1 CHs (7), allowing more release of ATP/glutamate and altering physiological functions of neurons (not depicted). Prenatal nicotine and postnatal high-fat/cholesterol diet could increase the release of glutamate and ATP from astrocytes via opening of Cx43 hemichannels (Cx43 HCs; 9). It is possible that microglia through the release of pro-inflammatory molecules (e.g., IL-1β and TNF-α) could contribute to the opening of astroglial Cx43 HCs via the activation of a p38MAPK/iNOS-dependent pathway.