| 12417644 |
Xu Y, Chiamvimonvat N, Vazquez AE, Akunuru S, Ratner N, Yamoah EN: Gene-targeted deletion of neurofibromin enhances the expression of a transient outward K+ current in Schwann cells: a protein kinase A-mediated mechanism. J Neurosci. 2002 Nov 1;22(21):9194-202.
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 (approximately 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. |
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