Cyclic guanosine 3´-5´-monophosphate (cGMP) is a ubiquitous intracellular second-messenger that modulates many physiological processes, from ion channel conductance to cell growth and apoptosis to cellular motility and contractility. Generated by seven homologous transmembrane guanylyl cyclase (GC) receptors and by intracellular GC (nitric oxide - activated GC), cGMP exerts its action through cGMP-gated ion channels, protein kinases (PKG I, PKG II), and cGMP-regulated phosphodiesterases (PDEs) that in turn hydrolyze cyclic nucleotides (cAMP and/or cGMP). Abnormalities at each step of the cGMP signaling cascade, from cGMP synthesis to its degradation, have been implicated in cardiovascular (arterial and pulmonary hypertension, cardiac hypertrophy), bone (achondroplasia) and retinal diseases (congetinal blindness). Hence, this cascade represents several potential targets for pharmacological therapies.
Research in the group of Michaela Kuhn focuses on elucidating the regulation and physiological functions of three membrane guanylyl cyclase receptors (GC-A, GC-B, GC-C) and their peptide ligands within the cardiovascular system, specifically in vascular endothelial and smooth muscle cells and cardiac myocytes. GC-A is activated by two cardiac hormones, atrial (ANP) and B-type natriuretic peptides (BNP), and is critically involved in the regulation of blood pressure/volume. GC-B is activated by C-type natriuretic peptide (CNP), a peptide which has local, paracrine functions in bone formation and endothelial regeneration. Finally, GC-C and its ligands (guanylin, uroguanylin) regulate ion and water transport in intestinal and renal epithelium. To dissect the various physiological functions and cellular signalling cascades of these ligand-receptor systems, in the past years we have developed various genetic mouse models with cell-specific deletion of these receptors or cGMP targets.
General structure of the membrane guanylyl cyclase receptors GC-A, GC-B and GC-C.
Membrane-bound receptor guanylyl cyclases, their ligands and main functions. Only for three of the membrane GCs, the extracellular ligands are known:
General structure and signaling by transmembrane guanylyl cyclase receptors. ECD, extracellular domain; KHD, kinase-homology domain; H, hinge region; CAT, catalytic domain which synthesizes cGMP. All particulate GCs form dimers.
For overview see:
Kuhn M. Structure, regulation and function of mammalian membrane guanylyl cyclase receptors, with focus on GC-A (2003) Circ Res 93:700-709.
Kuhn M. Molecular physiology of natriuretic peptide signalling (2004). Basic Res Cardiol 99: 76-82.
Kuhn M. Physiology of natriuretic peptides: insights from genetically modified mice (2005). Peptides 26:1078-1085.
Kuhn M. Function and dysfunction of mammalian membrane guanylyl cyclase receptors: lessons from genetic mouse models and implications for human diseases (2009). Handbook of Experimental Pharmacology 191:47-69.
For our recent observations about the regulation of guanylyl cyclase-A (GC-A) by alternative splicing and (de)phosphorylation see:
Hartmann M, Skryabin BV, Müller T, Gazinski A, Schröter J, Gaßner B, Nikolaev VO, Bünemann M, Kuhn M. (2008) Alternative splicing of the guanylyl cyclase-a receptor modulates atrial natriuretic peptide signalling. J Biol Chem 283:28313-28320.
Schröter J, Zahedi RP, Hartmann M, Gaßner B, Gazinski A, Waschke J, Sickmann A, Kuhn M. (2010) Homologous desensitization of guanylyl cyclase A, the receptor for atrial natriuretic peptide, is associated with a complex phosphorylation pattern. FEBS J 277:2440-2453.