Regulation of functional nitric oxide synthase-1 expression in cerebellar granule neurons by heregulin is...

The neuregulins, and the ErbB family of tyrosine kinase receptors, play important roles in the development of the nervous system. Recently, the C-terminal region of the ErbB4 receptor has been reported to associate with domains of post-synaptic density proteins. The latter are, in turn, known to assemble nitric oxide synthase (NOS)-1 at cell junctions. Previously, we showed that heregulin can up-regulate the expression of NOS-1 via the ErbB4 receptor in cerebellar granule cell cultures. We have now determined that this up-regulation is post-transcriptional, and results in an associated increase in NOS activity in these neurons. Furthermore, we find that heregulin activates both MAP kinase and phosphoinositide 3 kinase (PI 3-K) in granule cells. While inhibition of MAP kinase reduces the ability of heregulin to up-regulate NOS-1 expression, a specific inhibitor of PI 3-K was without effect. Our results suggest that NO could mediate some of the downstream effects of heregulin in the nervous system.