NMS Activators

Chemical activators of NMS can initiate a series of intracellular events leading to its activation through phosphorylation. Forskolin, by activating adenylyl cyclase, elevates cAMP levels within the cell. This rise in cAMP leads to the activation of protein kinase A (PKA), which then can phosphorylate NMS, altering its activity state. Similarly, dibutyryl cAMP, a cAMP analog, directly stimulates PKA, which in turn can target NMS for phosphorylation. Ionomycin, by increasing the intracellular calcium concentration, activates calcium-dependent protein kinases, such as CaMKII, that can also phosphorylate and activate NMS. The calcium-binding protein calmodulin, once associated with calcium, can activate kinases including CaMKII, further supporting the phosphorylation of NMS. Thapsigargin contributes to this cascade by inhibiting the SERCA pump, thereby elevating cytosolic calcium levels and potentially leading to the activation of these same calcium-dependent kinases.

Phorbol 12-myristate 13-acetate (PMA) directly stimulates protein kinase C (PKC) which is known to phosphorylate serine and threonine residues on target proteins including NMS. Okadaic Acid, by inhibiting protein phosphatases 1 and 2A, prevents the dephosphorylation of NMS, ensuring that the phosphorylation state and thus the activity of NMS is maintained. Anisomycin activates MAP kinase pathways, leading to the phosphorylation of a variety of proteins, with NMS being among the potential targets. Epidermal Growth Factor (EGF) activates the MAPK/ERK pathway, which includes a cascade of kinases capable of phosphorylating NMS. Inhibition of certain kinases can also indirectly lead to the activation of NMS. Both Bisindolylmaleimide I, a PKC inhibitor, and SB 203580, a p38 MAP kinase inhibitor, can result in the compensatory activation of other kinases within the cell, which can lead to the phosphorylation and consequent activation of NMS. In sum, multiple signaling pathways can converge on the phosphorylation and activation of NMS, mediated by a diverse array of chemical activators.