Regulation of functional nitric oxide synthase‐1 expression in cerebellar granule neurons by heregulin is post‐transcriptional, and involves mitogen‐activated protein kinase

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Abstract
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.