NO as a multimodal transmitter in the brain: discovery and current status.

NO operates throughout the brain as an intercellular messenger, initiating its varied physiological effects by activating specialized GC-coupled receptors, resulting in the formation of cGMP. In line with the widespread expression of this pathway, NO participates in numerous different brain functions. This review gives an account of the discovery of NO as a signalling molecule in the brain, experiments that originated in the search for a mysterious cGMP-stimulating factor released from central neurones when their NMDA receptors were stimulated, and summarizes the subsequent key steps that helped establish its status as a central transmitter. Currently, various modes of operation are viewed to underlie its diverse behaviour, ranging from very local signalling between synaptic partners (in the orthograde or retrograde directions) to a volume-type transmission whereby NO synthesized by multiple synchronous sources summate spatially and temporally to influence intermingled neuronal or non-neuronal cells, irrespective of anatomical connectivity. LINKED ARTICLES: This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc.