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Signaling and distribution of NPR-Bi, the human splice form of the natriuretic peptide receptor type B

Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, D-48149 Münster, Germany

Submitted 6 February 2003 ; accepted in final form 21 April 2003

Recently, we described a splice variant of the human natriuretic peptide receptor type B (NPR-Bi) in human proximal tubule cells [immortalized human kidney epithelial cells (IHKE-1) that lacks a functional guanylate cyclase domain (Hirsch JR, Meyer M, Mägert HJ, Forssmann WG, Mollerup S, Herter P, Weber G, Cermak R, Ankorina-Stark I, Schlatter E, and Kruhøffer M. J Am Soc Nephrol 10: 472–480, 1999). Its signaling pathway does not include cGMP, cAMP, or Ca²⁺ but leads to inhibition of K⁺ channels. In patch-clamp experiments, effects of tyrosine kinase receptor blockers on C-type natriuretic peptide (CNP)-mediated depolarizations of membrane voltages (V_m) of IHKE-1 cells were tested. The epidermal growth factor (EGF) receptor blocker genistein (10 µM) abolished the effect of CNP (0.2 ± 0.4 mV, n = 7), and comparable results were obtained with 10 µM daidzein (n = 8). Aminogenistein (10 µM, n = 5) and tyrphostin AG1295 (10 µM, n = 5) had no significant effects. EGF (1 nM) hyperpolarized cells by –5.3 ± 0.8 mV (n = 5). This effect was completely blocked by genistein or daidzein. The Cl^– channel blocker NPPB (10 µM, n = 5) inhibited the EGF-mediated hyperpolarization. mRNA expression of NPR-B and NPR-Bi shows reversed patterns along the human nephron. NPR-B is highly expressed in glomeruli and proximal tubules, whereas NPR-Bi shows strong signals in the distal nephron. Expression of NPR-Bi in the cortical collecting duct was also confirmed with immunohistochemistry. In other human tissues, NPR-Bi shows strongest expression in pancreas and lung, whereas in the heart and liver NPR-B is the dominating receptor. In conclusion, CNP inhibits an apical K⁺ channel in IHKE-1 cells independently of cGMP and so far this effect can only be blocked by genistein and daidzein. Tyrosine phosphorylation might be the missing link in the signaling pathway of CNP/NPR-Bi.

C-type natriuretic peptide; signal transduction; tyrosine kinase; patch clamp analysis; proximal tubule; kidney

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