期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 291, 期 5, 页码 L993-L1004出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00191.2005
关键词
pulmonary arterial hypertension; patch clamp; membrane potential
资金
- NHLBI NIH HHS [R01 HL066012, HL-054043, HL-066012, HL-064945] Funding Source: Medline
Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 291: L993-L1004, 2006. First published June 30, 2006; doi:10.1152/ajplung.00191.2005.-Activity of voltage-gated K+ (K-V) channels in pulmonary artery smooth muscle cells (PASMC) plays an important role in control of apoptosis and proliferation in addition to regulating membrane potential and pulmonary vascular tone. Bone morphogenetic proteins (BMPs) inhibit proliferation and induce apoptosis in normal human PASMC, whereas dysfunctional BMP signaling and downregulated K-V channels are involved in pulmonary vascular medial hypertrophy associated with pulmonary hypertension. This study evaluated the effect of BMP-2 on K-V channel function and expression in normal human PASMC. BMP-2 (100 nM for 18-24 h) significantly (> 2-fold) upregulated mRNA expression of KCNA5, KCNA7, KCNA10, KCNC3, KCNC4, KCNF1, KCNG3, KCNS1, and KCNS3 but downregulated ( at least 2-fold) KCNAB1, KCNA2, KCNG2, and KCNV2. The most dramatic change was the > 10-fold downregulation of KCNG2 and KCNV2, two electrically silent gamma-subunits that form heterotetramers with functional KV channel alpha-subunits (e.g., KCNB1-2). Furthermore, the amplitude and current density of whole cell K-V currents were significantly increased in PASMC treated with BMP-2. It has been demonstrated that K+ currents generated by KCNB1 and KCNG1 ( or KCNG2) or KCNB1 and KCNV2 heterotetramers are smaller than those generated by KCNB1 homotetramers, indicating that KCNG2 and KCNV2 (2 subunits that were markedly downregulated by BMP-2) are inhibitors of functional KV channels. These results suggest that BMP-2 divergently regulates mRNA expression of various KV channel alpha-, beta-, and gamma-subunits and significantly increases whole cell KV currents in human PASMC. Finally, we present evidence that attenuation of c-Myc expression by BMP-2 may be involved in BMP-2-mediated increase in K-V channel activity and regulation of KV channel expression. The increased KV channel activity may be involved in the proapoptotic and/or antiproliferative effects of BMP-2 on PASMC.
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