Endocrine Abstracts

Despite being identified almost two decades ago, the biological roles for C-type natriuretic peptide (CNP) have remained poorly elucidated. Both CNP and GC-B are highly conserved from flies and fish to humans. Recent investigations involving the disruption of the CNP gene (Nppc) or that of its GC-B receptor (Npr2) implicate a role for CNP and GC-B in bone formation and growth. Intriguingly, CNP and GC-B knock-out mouse models also exhibited pituitary growth hormone deficiency. Our previous and ongoing studies have focussed on the pituitary natriuretic peptide system, given the relatively high levels of CNP expression within the anterior pituitary. Expression studies, using established pituitary cell lines (αT3-1, LβT2 and GH3) and primary rodent pituitary tissue reveal expression of CNP/GC-B components, including GC-B1/2/3 splice variants. In the first characterisation studies of CNP/GC-B expression in human pituitary tumours, GC-B1 expression appears widespread throughout tumours of different origins, although GC-B2 and CNP expression appears far more selective. Functional studies investigating the down-stream consequences of GC-B activation in pituitary cells have revealed the novel observation that non-cyclic GMP signalling can occur directly via GC-B receptors. In GH3 and LβT2 cells, CNP potently stimulates phosphorylation of ERK, p38 and JNK members of the MAPK family, resulting in increased gene transcription. SiRNA silencing of GC-B expression in GH3 cells leads to a complete loss of these effects. The lack of requirement for cGMP signalling in mediating the effects on MAPK pathways is further enhanced by the failure of either ANP or dibutryl-cGMP to mimic the CNP effects on MAPK phosphorylation. Collectively, our studies have unmasked a fundamentally novel signalling property of the GC-B receptor that may have widespread consequences for natriuretic peptide signalling in other target tissues, such as bone, endothelium and glia. This may reveal novel biological roles for CNP throughout the endocrine system.