CHCHD5 Activators

Chemical activators of CHCHD5 function through various intracellular signaling cascades to modulate its activity. S-nitrosoglutathione, YC-1, and Zaprinast all have the common endpoint of elevating intracellular cGMP levels. S-nitrosoglutathione acts as a nitric oxide donor, enhancing soluble guanylyl cyclase activity which synthesizes cGMP. YC-1 amplifies this effect by sensitizing guanylyl cyclase to nitric oxide, further boosting cGMP production. Zaprinast extends the presence of cGMP in the cell by inhibiting its breakdown via phosphodiesterase 5. The increased levels of cGMP activate protein kinase G (PKG), which, upon activation, can phosphorylate CHCHD5, leading to its functional activation. Similarly, Forskolin raises intracellular cAMP levels by directly stimulating adenylyl cyclase. Elevated cAMP activates protein kinase A (PKA), which can then target CHCHD5 for phosphorylation if it is a substrate for PKA. IBMX and Vinpocetine also contribute to the elevation of cAMP and cGMP levels, albeit through a different mechanism. IBMX inhibits a broad range of phosphodiesterases, whereas Vinpocetine selectively inhibits PDE1, both resulting in increased cAMP and cGMP concentrations and subsequent activation of PKA and PKG, leading to phosphorylation of CHCHD5.

Calcium signaling is another pathway through which CHCHD5 activation can occur. Ionomycin and A23187 are calcium ionophores that increase intracellular calcium levels. This rise in calcium can activate calmodulin-dependent kinases capable of phosphorylating CHCHD5. Thapsigargin works indirectly by inhibiting the SERCA pump, leading to an increase in cytosolic calcium levels, which similarly activates calcium-dependent kinases that may target CHCHD5. Additionally, Anisomycin activates stress-activated protein kinases like JNK, which can lead to downstream phosphorylation of CHCHD5. Phorbol 12-myristate 13-acetate (PMA) operates through a different pathway by activating protein kinase C (PKC), which phosphorylates a variety of proteins, potentially including CHCHD5 if it is among its substrates. Lastly, Dibutyryl-cAMP, a cAMP analog that readily diffuses into cells, directly activates PKA, thus promoting the phosphorylation and activation of CHCHD5. Each chemical, through its unique mechanism, modulates signaling pathways that converge on the phosphorylation and subsequent activation of CHCHD5.