TY - JOUR
T1 - Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells
AU - Fantozzi, Ivana
AU - Platoshyn, Oleksandr
AU - Wong, Ada H.
AU - Zhang, Shen
AU - Remillard, Carmelle V.
AU - Furtado, Manohar R.
AU - Petrauskene, Olga V.
AU - Yuan, Jason X.J.
PY - 2006/11/23
Y1 - 2006/11/23
N2 - Activity of voltage-gated K+ (KV) 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 KV channels are involved in pulmonary vascular medial hypertrophy associated with pulmonary hypertension. This study evaluated the effect of BMP-2 on KV 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 γ-subunits that form heterotetramers with functional KV channel α-subunits (e.g., KCNB1-2). Furthermore, the amplitude and current density of whole cell KV 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 K V channel α-, β-, and γ-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 KV 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.
AB - Activity of voltage-gated K+ (KV) 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 KV channels are involved in pulmonary vascular medial hypertrophy associated with pulmonary hypertension. This study evaluated the effect of BMP-2 on KV 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 γ-subunits that form heterotetramers with functional KV channel α-subunits (e.g., KCNB1-2). Furthermore, the amplitude and current density of whole cell KV 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 K V channel α-, β-, and γ-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 KV 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.
KW - Membrane potential
KW - Patch clamp
KW - Pulmonary arterial hypertension
UR - http://www.scopus.com/inward/record.url?scp=33751087216&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33751087216&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00191.2005
DO - 10.1152/ajplung.00191.2005
M3 - Article
C2 - 16815889
AN - SCOPUS:33751087216
VL - 291
SP - L993-L1004
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 1040-0605
IS - 5
ER -