Supplementary Figure 15: PDE3A and its signal transductions.
From: PDE3A mutations cause autosomal dominant hypertension with brachydactyly
Scheme for the involvement of PDE3A in VSMCs and chondrocytes. In VSMCs, the myosin light chain kinase (MLCK) and the myosin light chain phosphatase (MLCP) act in concert to phosphorylate and dephosphorylate the myosin light chain (MLC) for vascular contraction and relaxation, respectively (Pfitzer, G. J. Appl. Physiol 91, 497-503, 2001). PKA and protein kinase G (PKG) activate VASP by phosphorylation of Ser157 and Ser239, respectively. Reduced VASP Ser157 phosphorylation and higher PDE3A activity were associated with enhanced VSMC proliferation that accounts for vessel wall hyperplasia (Zhao, H., Guan, Q., Smith, C.J. & Quilley, J. et al. Eur. J. Pharmacol. 590, 29-35, 2008). Full-length PTHrP stimulated whereas PTHrP peptide (1–36) repressed VSMC proliferation (Song, G.J., Fiaschi-Taesch, N. & Bisello, A. Mol. Endocrinol. 23, 1681-1680, 2009). CREB binding to the PTHLH promoter regulates PTHLH expression in a cAMP-dependent manner. The encoded protein PTHrP transduces signals through the PTH1R (PTH/PTHrP) receptor in chondrocytes and activates the heterotrimeric G protein Gs, thereby stimulating adenylate cyclase (AC) to produce cAMP (Bastepe, M. et al. Proc. Natl. Acad. Sci. USA 101, 14794–14799, 2004). Because PDE3A hydrolyses cAMP, PKA is regulated in a cAMP-dependent manner and activates CREB, which in turn regulates PTHLH expression (Chilco, P.J., Leopold, V. & Zajac, J.D. Mol. Cell. Endocrinol.138, 173–184, 1998).
