Nitric oxide neurons and neurotransmission

Nitric oxide was identified as a biological intercellular messenger just over 20 years ago, and its presence and potential importance in the nervous system was immediately noted. With the cloning of NO synthase and the physiological NO receptor soluble guanylyl cyclase, a variety of histochemical methods quickly led to a rather complete picture of where NO is produced and acts in the nervous system. However, the details regarding the subcellular localization of NO synthase and the identity of its molecular binding partners require further clarification. Although the hypothesis that calcium influx via activation of NMDA receptors is a key trigger for NO production has proven very popular and led to suggested roles for NO in synaptic plasticity, there is little direct evidence to support this notion. Instead, studies from the peripheral nervous system indicate a key role for voltage-sensitive calcium channels in regulating NO synthase activity. A similar mechanism may also be important in central neurons, and it remains an important task to identify the precise sources of calcium regulating NO production in specific NO neurons. Also, although cGMP production appears to mediate the physiological signaling by NO, the specific roles of cGMP-dependent ion channels, protein kinases and phosphodiesterases in mediating NO action remain to be determined.