TMEM146 Activators

Chemical activators of TMEM146 can engage multiple cellular mechanisms to elicit activation of the protein. Forskolin, for example, operates by directly activating adenylyl cyclase, which catalyzes the conversion of ATP to cAMP. The elevated levels of cAMP in turn activate protein kinase A (PKA), which is known to phosphorylate a variety of proteins, potentially including TMEM146. This phosphorylation can change the conformation of TMEM146, leading to its functional activation. Similarly, Phorbol 12-myristate 13-acetate (PMA) can activate protein kinase C (PKC), which is another kinase capable of phosphorylating TMEM146, thereby potentially promoting its active state. Ionomycin functions by increasing intracellular calcium concentrations, which could activate calcium-dependent kinases. These kinases, upon activation, can target TMEM146, leading to its phosphorylation and subsequent activation. Calyculin A, by inhibiting protein phosphatases 1 and 2A, prevents the dephosphorylation of proteins, which would otherwise reverse the phosphorylation mediated activation of proteins including TMEM146.

Further, Anisomycin activates stress-activated protein kinases which may cascade down to phosphorylate and activate TMEM146, while Thapsigargin by inhibiting the SERCA pump, indirectly leads to an increase in intracellular calcium that can activate PKC, which in turn could phosphorylate and activate TMEM146. Bryostatin 1, through its modulation of PKC, can lead to similar phosphorylation and activation outcomes for TMEM146. Fusicoccin's stabilization of 14-3-3 proteins interaction with target proteins could influence the activity state of TMEM146, presumably by enhancing its phosphorylation and activation. Vanadate, a tyrosine phosphatase inhibitor, can enhance phosphorylation of proteins including TMEM146, resulting in activation. Hydrogen Peroxide can activate various kinases via oxidative stress pathways, which may include those that phosphorylate TMEM146. Zinc Pyrithione, through the release of zinc ions, can activate kinases that phosphorylate and activate TMEM146. Lastly, Okadaic Acid by inhibiting protein phosphatases, can lead to hyperphosphorylation of proteins, which may include TMEM146, thereby maintaining its active form.