Recently we described a splice variant of the human natriuretic peptide receptor type B, NPR-Bi, in human proximal tubule cells (IHKE-1) which lacks a functional guanylate cyclase domain (8). Its signaling pathway does not include cGMP, cAMP or Ca²⁺ but leads to inhibition a K⁺-channels. In patch clamp experiments effects of tyrosine kinase receptor blocker on CNP-mediated depolarization of membrane voltage (V_m) of IHKE-1 cells were tested. The EGF receptor blocker genistein (10 µM) abolished the effect of CNP (0.2±0.4 mV, n=7), comparable result 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 show reversed patterns along the human nephron. NPR-B is highly expressed in glomeruli and proximal tubules, NPR-Bi shows strong signals in the distal nephron. Expression of NPR-Bi in the CCD was also confirmed with immunohistochemistry. In other human tissues NPR-Bi shows strongest expression in pancreas and lung while in 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 signalling pathway of CNP/NPR-Bi.