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The Journal of Neuroscience, November 1, 2002, 22(21):9194-9202

Gene-Targeted Deletion of Neurofibromin Enhances the Expression of a Transient Outward K⁺ Current in Schwann Cells: A Protein Kinase A-Mediated Mechanism

Yanfang Xu^{1, 2, 4}, Nipavan Chiamvimonvat², Ana E. Vázquez¹, Shailaja Akunuru³, Nancy Ratner³, and Ebenezer N. Yamoah¹

¹ Center for Neuroscience, Department of Otolaryngology, and ² Department of Medicine, University of California, Davis, Davis, California 95616, ³ Department of Cell Biology, Neurobiology, and Anatomy, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267, and ⁴ Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei 050091, China

Mutations in the neurofibromatosis type 1 gene predispose patients to develop benign peripheral nerve tumors (neurofibromas) containing Schwann cells (SCs). SCs from neurofibromatosis type-1 gene (Nf1) null mutant mice showed increased levels of Ras-GTP and cAMP. The proliferation and differentiation of SCs are regulated by Ras-GTP and cAMP-mediated signaling, which have been linked to expression of K⁺ channels. We investigated the differential expression of K⁺ currents in Nf1 null mutant SCs (Nf1/) and their wild-type (Nf1+/+) counterparts and determined the mechanisms underlying the differences. The current densities of the sustained component of K⁺ currents were similar in the two genotypes. However, Nf1/ SCs showed a significant increase (~1.5-fold) in a 4-aminopyridine-sensitive transient outward K⁺ current (I_A). Nonstationary fluctuation analysis revealed a significant increase in the number of functional channels in the null mutant cells. When the involvement of the Ras pathway in the modulation of the K⁺ current was examined using adenoviral-mediated gene transfer of a dominant-negative H-Ras N17 or the known H-Ras inhibitor (L-739,749), an additional increase in I_A was observed. In contrast, protein kinase A (PKA) inhibitors, H89 and [PKI(2-22)amide] attenuated the enhancement of the current in the Nf1/ cells, suggesting that the increase in I_A was mediated via activation of protein kinase A. The unitary conductance of the channel underlying I_A was unaltered by inhibitors of PKA. Activation of I_A is thus negatively regulated by Ras-GTP and positively regulated by PKA.

Key words: K⁺ channels; protein kinase A; neurofibromin NF1; glia; Schwann cells; voltage clamp

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22219194-09$05.00/0

This article has been cited by other articles:

				M. Zhang, X.-W. Fei, Y.-L. He, G. Yang, and Y.-A. Mei Bradykinin inhibits the transient outward K+ current in mouse Schwann cells via the cAMP/PKA pathway Am J Physiol Cell Physiol, June 1, 2009; 296(6): C1364 - C1372. [Abstract] [Full Text] [PDF]

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