Excitable Astrocytes: Ca2+- and cAMP-Regulated Exocytosis

During neural activity, neurotransmitters released at synapses reach neighbouring cells, such as astrocytes. These get excited via numerous mechanisms, including the G protein coupled receptors that regulate the cytosolic concentration of second messengers, such as Ca2+ and cAMP. The stimulation of these pathways leads to feedback modulation of neuronal activity and the activity of other cells by the release of diverse substances, gliosignals that include classical neurotransmitters such as glutamate, ATP, or neuropeptides. Gliosignal molecules are released from astrocytes through several distinct molecular mechanisms, for example, by diffusion through membrane channels, by translocation via plasmalemmal transporters, or by vesicular exocytosis. Vesicular release regulated by a stimulus-mediated increase in cytosolic second messengers involves a SNARE-dependent merger of the vesicle membrane with the plasmalemma. The coupling between the stimulus and vesicular secretion of gliosignals in astrocytes is not as tight as in neurones. This is considered an adaptation to regulate homeostatic processes in a slow time domain as is the case in the endocrine system (slower than the nervous system), hence glial functions constitute the gliocrine system. This article provides an overview of the mechanisms of excitability, involving Ca2+ and cAMP, where the former mediates phasic signalling and the latter tonic signalling. The molecular, anatomic, and physiologic properties of the vesicular apparatus mediating the release of gliosignals is presented.