| Lincoln R. Potter |
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Research Description
Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide comprise a family of endocrine/paracrine factors that decrease blood pressure, inhibit cardiac hypertrophy and stimulate long bone growth (Fig. 1). In the clinic, BNP is the best humeral indicator of congestive heart failure known, and recombinant BNP (nesiritide), is an FDA approved drug for the treatment of acute decompensated congestive heart failure. The primary signaling molecules for these peptides are natriuretic peptide receptor A and B (NPR-A and B). Homozygous inactivating mutations within NPR-B cause a form of dwarfism called acromesomelic dysplasia type Maroteaux, whereas single allele mutations reduce stature.
Fig. 1 Naturiuretic peptide expression, processing and structure. |
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 Potter, L.R., et al. Endocr. Rev. 2006;27:42-72 |
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Both NPR-A and NPR-B consist of an amino-terminal extracellular ligand binding domain, a single membrane-spanning region, an intracellular kinase homology domain (KHD) and a carboxyl-terminal guanylyl cyclase catalytic domain (Fig. 2).
Fig 2. Natriuretic peptide receptor topology and ligand preferences |
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The activation of these enzymes results in the synthesis of the second messenger, cyclic GMP, which activates protein kinases, phosphodiesterases and ion channels (Fig. 3). We have shown that phosphorylation of serines and threonines within the kinase homology domains of these receptors is required for hormonal stimulation and that dephosphorylation mediates acute receptor desensitization. Recently, we reported that NPR-A downregulation (loss of receptor protein) explains reduced renal ANP responses observed in response to chronic stimuli like heart failure. In addition, we discovered that NPR-B, not NPR-A, is the major natriuretic peptide receptor in the failed heart, which implicates NPR-B as a potential cardiovascular drug target.
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Fig. 3. Cyclic GMP effectors, cGMP mediates its effects by binding three known classes of proteins: cGMP-gated ion channels, cGMP-dependent protein kinases (type I(alpha, I(beta) or type II and phosphodiesterases (PDEs)
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We are currently investigating: 1) the regulation of NPR-A and NPR-B in heart failure and hypertension using animal models as well as human tissue, 2) how NPR-B and/or NPR-A are inhibited by vasoactive hormones and growth factors, 3) the mechanics and pathway of NPR-A downregulation in cultured cells and rodents, 4) the prevalence and effect of single nucleotide polymorphisms on the human NPR-A gene, 5) the identity of the natriuretic peptide receptor kinase(s), and 6) the creation of novel natriuretic peptides as potential "second generation" versions of nesiritide.
Recent Publications
Antos LK, Potter LR. Adenine nucleotides decrease the apparent Km of endogenous natriuretic peptide receptors for GTP. Am J Physiol Endocrinol Metab. 2007 Sep 11;
Dickey DM, Flora DR, Bryan PM, Xu X, Chen Y, Potter LR. Differential regulation of membrane guanylyl cyclases in congestive heart failure: natriuretic peptide receptor (NPR)-B, Not NPR-A, is the predominant natriuretic peptide receptor in the failing heart.
Endocrinology. 2007 Jul;148(7):3518-22. Epub 2007 Apr 5.
Bryan PM, Xu X, Dickey DM, Chen Y, Potter LR. Renal Hyporesponsivness to atrial natriuretic peptide in congestive heart failure resultes from reduced atrial natururetic peptide receptor concentrations. Am J Physiol Renal Physiol. 2007 May;292(5):F1636-44.
Bryan PM, Smirnov D, Smolenski A, Feil S, Feil R, Hofmann F, Lohmann S, Potter LR. A sensitive method for determining the phosphorylation status of natriuretic peptide receptors: cGK-Ialpha does not regulate NPR-A. Biochemistry. 2006 Jan 31;45(4):1295-303.
Olney RC, Bukulmez H, Bartels CF, Prickett TC, Espiner EA, Potter LR, Warman ML. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab. 2006 Apr;91(4):1229-32. Epub 2005 Dec 29.
Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006 Feb;27(1):47-72. Epub 2005 Nov 16. Review.
Potter LR. "Corination" of the proANP converting enzyme. Cell Metab. 2005 Feb;1(2):88-90.
Antos LK, Abbey-Hosch SE, Flora DR, Potter LR. ATP-independent activation of natriuretic peptide receptors. J Biol Chem. 2005 Jul 22;280(29):26928-32. Epub 2005 May 23.
Fan D, Bryan PM, Antos LK, Potthast RJ, Potter LR. Down-regulation does not mediate natriuretic peptide-dependent desensitization of natriuretic peptide receptor (NPR)-A or NPR-B: guanylyl cyclase-linked natriuretic peptide receptors do not internalize. Mol Pharmacol. 2005 Jan;67(1):174-83. Epub 2004 Sep 30.
Potthast R, Abbey-Hosch SE, Antos LK, Marchant JS, Kuhn M, Potter LR. Calcium-dependent dephosphorylation mediates the hyperosmotic and lysophosphatidic acid-dependent inhibition of natriuretic peptide receptor-B/guanylyl cyclase-B. J Biol Chem. 2004 Nov 19;279(47):48513-9. Epub 2004 Sep 14.
Abbey-Hosch SE, Cody AN, Potter LR. Sphingosine-1-phosphate inhibits C-type natriuretic peptide activation of guanylyl cyclase B (GC-B/NPR-B). Hypertension. 2004 May;43(5):1103-9. Epub 2004 Mar 22.
Abbey SE, Potter LR. Lysophosphatidic acid inhibits C-type natriuretic peptide activation of guanylyl cyclase-B. Endocrinology. 2003 Jan;144(1):240-6
Abbey SE, Potter LR. Vasopressin-dependent inhibition of the C-type natriuretic peptide receptor, NPR-B/GC-B, requires elevated intracellular calcium concentrations. J Biol Chem. 2002 Nov 8;277(45):42423-30. Epub 2002 Aug 23.
Bryan PM, Potter LR. The atrial natriuretic peptide receptor (NPR-A/GC-A) is dephosphorylated by distinct microcystin-sensitive and magnesium-dependent protein phosphatases. J Biol Chem. 2002 May 3;277(18):16041-7.
Lab Photo
Deborah Dickey, Darcy Flora, Lincoln Potter, Laura Antos and Andrea Yoder |
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