Endocrine Abstracts

The local biological activity of the natriuretic peptides ANP, BNP and CNP is regulated by changes in the activity of their guanylyl cyclase (GC)-containing receptors GC-A and GC-B, by the so-called natriuretic peptide clearance receptor NPR-C and by membrane-bound ectoproteases. Activity of GCs is regulated by alterations in the extent of receptor phosphorylation. Dephosphorylation decreases natriuretic peptide-induced GC activity. This mechanism is used for desensitization in response to elevated ligand exposure.

In MA-10 Leydig cells, homologous desensitization of GC-A, i.e. desensitization by its ligand ANP, and heterologous desensitization by a GC-independent mechanism were found to occur in the same cell and to be regulated by different signalling pathways. MA-10 cells lack the CNP receptor GC-B. To investigate potential interactions in GC-A- and GC-B-co-expressing cells, αT3 cells were studied, showing homologous desensitization of GC-A, but not of GC-B. Next, desensitization of GC-B by ANP/GC-A and of GC-A by CNP/GC-B were investigated. ANP did not affect GC-B activity. Most surprisingly, however, CNP augmented GC-A activity, using a GC-B- and cAMP-dependent protein kinase-mediated mechanism.

Such a CNP/GC-B-mediated sensitization of GC-A was also detectable in GC-A- and GC-B-expressing vascular smooth muscle cells. By this mechanism, CNP was shown to enhance the vasorelaxing potency of ANP/GC-A in pre-contracted vasculature. Moreover, vessels, pre-incubated with ANP, only showed slight relaxation, indicating that smooth muscle GC-A is also sensitive to desensitization. CNP was found to relieve this desensitization.

Our results revealed a novel signalling pathway, by which CNP can increase the hormone-sensitivity of GC-A. This mechanism is apparently present and active in the vasculature to regulate the vasodilatory potency of ANP. Desensitization of GC-A, expected to take place under conditions of elevated ANP plasma levels, can be relieved by CNP/GC-B signalling. Data suggests a considerable therapeutic potential of GC-B agonists.