Voltage-gated K⁺ (Kv) channel activity in PASMC plays an important role in regulating apoptosis and proliferation, as well as membrane potential and vascular tone. Bone morphogenetic proteins (BMP) inhibit proliferation and induce apoptosis in normal PASMC, whereas dysfunctional BMP signaling and downregulated Kv channels are involved in pulmonary vascular medial hypertrophy associated with pulmonary hypertension. BMP-2 (100 nM for 18-24 hrs) significantly (>2-fold) upregulated mRNA expression of KCNA5, KCNA7, KCNA10, KCNC3, KCNC4, KCNF1, KCNG3, KCNS1, and KCNS3, whereas it 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 Kv channel 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 (two 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 // 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.