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Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K⁺ channels in human pulmonary artery smooth muscle cells

¹Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Diego, La Jolla, and ²Applied Biosystems, Foster City, California

Submitted 27 April 2005 ; accepted in final form 28 June 2006

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 -subunits that form heterotetramers with functional K_V channel -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 K_V channels. These results suggest that BMP-2 divergently regulates mRNA expression of various K_V channel -, -, and -subunits and significantly increases whole cell K_V 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 K_V channel expression. The increased K_V channel activity may be involved in the proapoptotic and/or antiproliferative effects of BMP-2 on PASMC.

pulmonary arterial hypertension; patch clamp; membrane potential

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