Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, we show that bone elongation is increased when NPR2 cannot be dephosphorylated and thus produces more cyclic GMP. By developing an in vivo imagin...

In former studies, raised urine cGMP levels have been reported to predict adverse outcome in cervical cancer. The main objective of the present study was to investigate the value of nitric oxide synthase (iNOS) and other members of the cGMP pathway as potential biomarkers for prognosis of cervical carcinoma. Tissue samples from 85 patients surgically treated for early-stage cervical carcinoma w...

Heat-stable enterotoxins (STa), which cause an acute secretory diarrhea, have been suggested to mediate their actions through the guanylyl cyclase-C (GC-C) receptor. The GC-C gene was disrupted by insertion of neo into exon 1 and subsequent homologous recombination. GC-C null mice contained no detectable GC-C protein. Intestine mucosal guanylyl cyclase activity was approximately 16-fold higher ...

The membrane and soluble guanylyl cyclases (sGCs) are key families of enzymes that produce the second messenger cGMP. Although both families recognize different ligands and have therefore different N-terminal input domains, they do have similar C-terminal output domains containing a coiled-coil domain and a guanylyl cyclase catalytic domain. We present here our latest structure-function studies...

Guanylyl cyclases (GCs) regulate many physiological processes by catalyzing the synthesis of the second messenger cGMP. The GC family consists of seven particulate GCs (pGCs) and a nitric oxide-activated soluble GC (sGC). Rat sGC α1β1 possesses much broader substrate specificity than previously assumed. Moreover, the exotoxins CyaA from Bordetella pertussis and edema factor (EF) from Bacillus a...

Guanylyl cyclases (GCs) and adenylyl cyclases (ACs) have fundamental roles in a wide range of cellular processes. Whereas GCs use GTP as a substrate to form cGMP, ACs catalyze the analogous conversion of ATP to cAMP. Previously, a model based on the structure of adenylate cyclase was used to predict the structure of the nucleotide-binding pocket of a membrane guanylyl cyclase, RetGC-1. Based on...

No data are available for the direct effect of C-type natriuretic peptide (CNP) on atrioventricular (AV) conduction in mammalian hearts. Thus we studied the dromotropic effects of CNP-22 injected into the AV node artery in autonomically decentralized hearts in open-chest, anesthetized dogs. CNP decreased AV interval (AV conduction time) in a dose-dependent manner with increase in coronary arter...

The NO receptor, NO-sensitive guanylyl cyclase, plays a key role in the NO/cGMP signal-transduction cascade. Two isoforms of the enzyme are currently known, the widely distributed vascular alpha1beta1 isoform and the neuronal alpha2beta1 isoform predominantly expressed in brain. Interaction with the PSD-95 (postsynaptic density protein-95) family of scaffolding proteins targets the neuronal alp...

The phosphodiesterase (3':5'-cyclic AMP 5'-nucleotidohydrolase, EC 3.1.4.17) inhibitor thepohylline enhances both the amplitude and duration of a long-lasting synaptic hyperpolarization in identified neuron R15 in Aplysia californica. Intraneuronal injection into R15 of glanylyl-imidodiphosphate, an adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activator, results in a deep...

OF THE MANY PHYSIOLOGICAL effects exerted by atrial natriuretic peptide (ANP), its direct influence on vascular tone seems to be the most puzzling. In the peripheral circulation, ANP binds to the extracellular ligand binding domain of the membrane-bound guanylyl cyclase isoform A (GC-A), which is widely expressed in vascular smooth muscle, to increase intracellular levels of cGMP (11). Activati...