Neuropharmacology

Biography

Biography: Xavier F. Figueroa

Abstract

Brain function depends on the coordination of neuronal activity and cerebral blood flow by a signaling mechanism known as neurovascular coupling. Neurotransmitters released during an increase in synaptic activity (e.g. glutamate) initiate a Ca2+ signaling in astrocytes, which activates the release of vasoactive factors from astrocytic endfeet to parenchymal arterioles. Then, changes in neuronal activity are coupled to local blood flow through regulation of arteriolar diameter. Although NO is one of the most important signaling molecules in vascular physiology, its participation in neurovascular coupling is controversial. However, astrocytes express the Ca2+-dependent NO-synthetizing enzymes eNOS and nNOS and NO modulates the activity of channels formed by connexins (gap junction channels and hemichannels) or pannexins, which coordinate the neurovascular coupling-associated astrocyte signaling. The participation of NO in the neurovascular coupling initated by metabotropic glutamate receptor (mGluR) stimulation was assessed in primary cultures of astrocytes and rat brain slices. NO production, vasomotor response of brain cortex arterioles, activity of connexin hemichannels and pannexin channels, changes in [Ca2+]i and ATP release were evaluated. The results indicate that NO, but unexpectedly, also Ca2+ homeostasis modulator 1 (CALHM1) channels, are essential for the astrocyte signaling that mediates neurovascular coupling. Stimulation of astrocytes mGluRs leads to NO-mediated activation of CALHM1 channels by S-nitrosylation, which evokes ATP release. The subsequent ATP-dependent purinergic receptor stimulation induces the opening of Cx43 hemichannels and Panx-1 channels, which contributes to the astrocytic Ca2+ signaling. These findings may provide clues to the design of new therapeutic strategies for the treatment of neurodegenerative diseases.