Receptor guanylyl cyclase (RGC) family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The mammalian genome encodes transmembrane and soluble receptor guanylyl cyclases, both of which have enzyme activities which convert guanosine-5'-triphosphate to the intracellular second messenger cyclic guanosine-3',5'-monophosphate (cyclic GMP).

The regulatory role of the kinase-homology domain in receptor guanylyl cyclases: nothing ‘pseudo’ about it!

The availability of genome sequence information and a large number of protein structures has allowed the cataloging of genes into various families, based on their function and predicted biochemical activity. Intriguingly, a number of proteins harbor changes in the amino acid sequence at residues, that from structural elucidation, are critical for catalytic activity. Such proteins have been categorized as ‘pseudoenzymes’. Here, we review the role of the pseudokinase (or kinase-homology) domain in receptor guanylyl cyclases. These are multidomain single-pass, transmembrane proteins harboring an extracellular ligand-binding domain, and an intracellular domain composed of a kinase-homology domain that regulates the activity of the associated guanylyl cyclase domain. Mutations that lie in the kinase-homology domain of these receptors are associated with human disease, and either abolish or enhance cGMP production by these receptors to alter downstream signaling events. This raises the interesting possibility that one could identify molecules that bind to the pseudokinase domain and regulate the activities of these receptors, in order to alleviate symptoms in patients harboring these mutations.

Sp1 mediates phorbol ester (PMA)-induced expression of membrane-bound guanylyl cyclase GC-A in human monocytic cells*

Cyclic guanosine monophosphate (cGMP) is synthesized by two types of enzymes: particulate (membrane-bound) guanylyl cyclases (pGCs) and soluble (cytosolic) guanylyl cyclases (sGCs). sGCs are activated primarily by binding of nitric oxide to their prosthetic heme group while pGCs are activated by binding of peptide ligands to their extracellular domains. One of them, pGC type A (GC-A) is activated by atrial and brain natriuretic peptides (ANP and BNP, respectively). Human monocytes isolated from peripheral blood mononuclear cells have been shown to have sGC expression without concomitant expression of GC-A. However, GC-A activity appears in monocytes under certain conditions but a molecular mechanism of GC‑A expression is still poorly understood. In this report we show that phorbol ester (PMA) induced transcription of the gene encoding GC-A in human monocytic THP-1 cells. Moreover, PMA-treated THP-1 cells have been found to raise cGMP content following treatment with ANP. Studies using pharmacological inhibitors of protein kinases have suggested involvement of protein kinase C (PKC), mitogen extracellular kinases (MEK1/2), and extracellular signal-regulated kinases (ERK1/2) in PMA-induced expression of the GC-A encoding gene in THP-1 cells. Finally, we show that PMA stimulated binding of Sp1 transcription factor to GC-rich DNA sequences and mithramycin A (a selective Sp1 inhibitor) inhibited expression of the GC-A mRNA in PMA-treated THP-1 cells. Taken together, our findings suggest that the PMA/PKC/MEK/ERK signaling pathway induces Sp1-mediated transcription of the GC-A encoding gene in human monocytic THP-1 cells.