Figure 1.

Reactive oxygen species (ROS) involvement in mitogen-activated protein kinases (MAPK) 1/3 activation by gonadotropin-releasing hormone (GnRH) and resolution in gonadotrope cells. Activation profiles of MAPK1/3 and DUSP1 as determined by phosphorylation in response to a single GnRH pulse [adapted from Ref. (35)]. GnRH receptor-signaling via G_aq/11 activates phospholipase C, leading to diacylglycerol (DAG) and IP₃ production. The DAG and IP₃-induced rise in intracellular Ca²⁺ activate both NOX and DUOX family members, resulting in increased ROS production. ROS stimulates MAPK1/3 activation by promoting Ras and Raf activation of the MEKn cascade ultimately targeting MAPK1/3. Oxidative activation of epidermal growth factor receptor (EGFR) contributes to MAPK1/3 activation through Raf. ROS may also transiently inactivate negative feedback through reversible oxidation of the DUSP active-site cysteine. ROS is normally reduced by peroxiredoxin (PRDX) by conversion of active reducing site cysteine thiol C–SH to sulfenic C–SOH. Sulfenic cysteine is recycled by thioredoxin (TRX) reduction. Excess ROS contributes to PRDX hyperoxidation that further oxidizes the sulfenic C–SOH to the sulfinic C–SOOH, which is reduced by the ATP-dependent reductase activity of sulfiredoxin 1 (SRXN1), preserving PRDX capacity but allowing transient DUSP inactivation. DUSP activity is resumed after ROS level declines, permitting feedback control of MAPK1/3. ROS activation of L-type VGCC promotes intracellular Ca²⁺ that supports exocytosis and activation of DUOX.