Competitive binding of musclin to natriuretic peptide receptor 3 with atrial natriuretic peptide

Musclin is a novel skeletal muscle-derived secretory factor that was isolated by our group. Musclin contains a region homologous to natriuretic peptides (NPs). This study investigated the interaction between musclin and NP receptors (NPRs). Musclin specifically bound to NPR3, but not to NPR1 or NPR2. Musclin and atrial natriuretic peptide (ANP) competed for binding to NPR3. We conducted binding assays using various synthetic musclin peptides and mutant musclin proteins. The first NP-homologous region in musclin (88LDRL91) and the second homologous region (117MDRI120) were responsible cooperatively for high-affinity binding to NPR3. The first NP-homologous region was more importantly associated with binding to NPR3, than the second homologous region. The competitive nature of musclin with ANP for the natriuretic clearance receptor NPR3 was also confirmed in vivo. We conclude that musclin binds to NPR3 competitively with ANP and may affect ANP concentrations in a local or systemic manner.

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The primary structure of the rat guanylyl cyclase A/atrial natriuretic peptide receptor gene

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)30520-3 ◽

1990 ◽

Vol 265 (33) ◽

pp. 20414-20420

Author(s):

M Yamaguchi ◽

L J Rutledge ◽

D L Garbers

Keyword(s):

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Guanylyl Cyclase ◽

Primary Structure ◽

Receptor Gene ◽

Natriuretic Peptide Receptor ◽

Peptide Receptor ◽

Atrial Natriuretic Peptide Receptor ◽

Atrial Natriuretic

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Allotopic antagonism of the non-peptide atrial natriuretic peptide (ANP) antagonist HS-142-1 on natriuretic peptide receptor NPR-A

Biochemical Journal ◽

10.1042/bj3620231 ◽

2002 ◽

Vol 362 (2) ◽

pp. 231-237 ◽

Cited By ~ 5

Author(s):

Hugo POIRIER ◽

Jean LABRECQUE ◽

Julie DESCHÊNES ◽

André DeLÉAN

Keyword(s):

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Mode Of Action ◽

Transmembrane Domain ◽

Peptide Binding ◽

Natriuretic Peptide Receptor ◽

Receptor Dimerization ◽

Peptide Receptor ◽

Peptide Binding Site ◽

Atrial Natriuretic

The microbial polysaccharide HS-142-1 has been documented as an antagonist of natriuretic peptides. It inhibits activation and peptide binding to both guanylate receptors natriuretic peptide receptor (NPR)-A and NPR-B, but has no effect on the non-cyclase receptor NPR-C. At first sight the effect of HS-142-1 on peptide binding appears to be surmountable, suggesting that it might be competitive despite its chemically divergent nature. We explored its mode of action on wild-type NPR-A (WT), on a disulphide-bridged constitutively active mutant (C423S) and on truncated mutants lacking either their cytoplasmic domain (ΔKC) or both the cytoplasmic and the transmembrane domains (ECD). On the WT, HS-142-1 inhibited atrial natriuretic peptide (ANP) binding with a pK value of 6.51±0.07 (Kd = 0.31μM). It displayed a similar effect on the C423S mutant (pK = 6.31±0.11), indicating that its action might not be due to interference with receptor dimerization. HS-142-1 also inhibited ANP binding to ΔKC with a pK of 7.05±0.05 (Kd = 0.089μM), but it was inactive on ANP binding to ECD at a concentration of 10−4M, suggesting that the antagonism was not competitive at the peptide-binding site located on the ECD and that the transmembrane domain might be required. HS-142-1 also enhanced dissociation of NPR-A-bound 125I-ANP in the presence of excess unlabelled ANP, implying an allotopic (allosteric) mode of action for the antagonist.

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