how prolonged cell depolarization can lead to EC release; however, there are other mechanisms that can give rise to EC release and CB1 activation. These include activation of other GPCRs, such as the metabotropic glutamate receptor 5 (mGluR5; Maejima et al., 2001; Varma et al., 2001), and activation of ligand-gated ion channels like the NMDA receptor (Ohno-Shosaku et al., 2007; Stella and Piomelli, 2001). These studies demonstrate that ECs act as retrograde neurotransmitters that serve to decrease synaptic transmission during periods of intense cellular activity.
