Regulation of Guanylyl Cyclase A and B by Hormones, ATP, and Phosphorylation
Guanylyl cyclase (GC)-A and B are homologous, peptide-activated, cGMP synthesizing enzymes that regulate blood pressure, heart size, long bone growth and oocyte maturation. Hence, they are desirable drug targets. However, lack of information about how this regulation takes place prevents the maximum therapeutic use of these enzymes for the treatment of cardiovascular, skeletal, and reproductive diseases.
Adenine nucleotides regulate GC-A and GC-B by binding unidentified intracellular high-affinity activation and low-affinity inhibitory sites through undefined mechanisms. Both receptors are highly phosphorylated in resting cells and dephosphorylated receptors are unresponsive to natriuretic peptides (NPs). Hormones that oppose the actions of NPs elevate intracellular calcium, which causes the dephosphorylation of all receptor phosphorylation sites. In contrast, activated protein kinase C (PKC) is hypothesized to phosphorylate a conserved receptor consensus site that reduces phosphorylation of a separate critical regulatory site.
The long-term objective of this project is to determine how hormones, adenine nucleotides, and phosphorylation regulate GC-A and GC-B. The project has four specific aims: determine how adenine nucleotides regulate GC-A and GC-B; identify how PKC inhibits GC-B; determine how disease-causing missense mutations affect GC-B function; and identify how hormones inhibit GC-B.
This project is significant because the successful completion of these specific aims will advance understanding of hormone-, adenine nucleotide- and phosphorylation-dependent regulation of GC-A and GC-B and may revealnew therapeutic targets.