Integration of cAMP and Ca2+ signaling pathways: Formation of a PDE1C and TrpC1 containing complex.

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Xiao, Hao
PDE1C , SOCC , proliferation , VSMC
The phenotypic modulation of vascular smooth muscle cells (VSMCs) from a “contractile/quiescent” to an “activated/synthetic” phenotype, with increased proliferative and migratory potential, is critical for the formation of advanced atherosclerotic lesions. Agents that regulate intracellular levels of the cyclic AMP (cAMP) and cyclic GMP (cGMP) have been shown to reduce VSMC migration and proliferation, and to reduce intimal thickening in response to vascular damage. Interestingly, expression of a specific cyclic nucleotide phosphodiesterase, namely PDE1C that is not expressed in contractile VSMCs is induced in activated human VSMCs and this directly impacts human VSMC phenotypic modulation. This study was undertaken to identify potential mechanism(s) by which PDE1C could impact VSMC phenotypic modulation and associated cellular functions. Overall, my data indicate that PDE1C controls store operated calcium (Ca2+) channel (SOCC) activity in activated human VSMCs. Indeed, expression of PDE1C increases store operated Ca2+ entry (SOCE), which in turn activates PDE1C. This linkage between PDE1C and the SOCC complex increases cytosolic [Ca2+] and activates cell proliferation. A potential human VSMC SOCC, the Transient receptor potential channel 1 (TrpC1), was shown to physically associate with PDE1C in HEK293T cells expressing these proteins heterologously, as well as in human aortic Smooth Muscle Cells (HASMCs), which natively express these proteins. In HEK293T cells, I also identified association of adenylyl cyclase 6 (AC6) and of the inositol-trisphosphate receptor (IP3R) iii with TrpC1. Interaction between TrpC1 and PDE1C in HASMCs is decreased upon activation of SOCE, suggesting PDE1C is activated after release from TrpC1-PDE1C complex. From these studies I have established a potential mechanism by which PDE1C signaling impacts SOCE and shown that a TrpC1-PDE1C complex may be important.
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