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N-methyl-d-aspartate receptors (NMDARs) are excitatory glutamatergic receptors that are fundamental for many neuronal processes, including synaptic plasticity. NMDARs are comprised of four subunits derived from heterogeneous subunit families, yielding a complex diversity in NMDAR form and function. The quadruply-liganded state of binding of two glutamate and two glycine molecules to the receptor drives channel gating, allowing for monovalent cation flux, Ca2+ entry and the initiation of Ca2+-dependent signalling. In addition to this ionotropic function, non-ionotropic signalling can be initiated through the exclusive binding of glycine or of glutamate to the NMDAR. This binding may trigger a transmembrane conformational change of the receptor, inducing intracellular protein-protein signalling between the cytoplasmic domain and secondary messengers. In this review, we outline signalling cascades that can be activated by NMDARs and propose that the receptor transduces signalling through three parallel streams: (i) signalling via both glycine and glutamate binding, (ii) signalling via glycine binding, and (iii) signalling via glutamate binding. This variety in signal transduction mechanisms and downstream signalling cascades complements the widespread prevalence and rich diversity of NMDAR activity throughout the central nervous system and in disease pathology.

Background Alterations in vascular relaxation have been reported in various models of hypertension. With its tonic activity, the NO/cGMP signalling cascade plays an important role in the regulation of the vascular tone. In blood vessels, NO is continuously being produced by the endothelial NO synthases (eNOS) which leads to cGMP production by stimulating the NO-sensitive guanylyl cyclases (NO-GCs). In vascular smooth muscle cells, two NO-GC isoforms, NO-GC1 and NO-GC2, mediate relaxation, with NO-GC1 being responsible for approximately 90% of the NO-stimulated cGMP formation. Deletion of eNOS or both NO-GCs abrogates endothelium-dependent relaxation and causes substantial hypertension. However, deletion of only NO-GC1 does not lead to hypertension despite a 50% reduction of endothelium-dependent relaxation.