Figure 2.

Major signalling pathways identified in ischaemic postconditioning (PostC). Several autacoid substances (adenosine, bradykinin, opioids, TNFα) are produced endogenously and act as triggers in PostC. These autacoids bind to G-protein-coupled receptors (GPCR) and stimulate RISK pathway which recruits PI3K/Akt and ERK, activates PKCɛ through eNOS/NO/PKG, and phosphorylates (inhibits) GSK3β, thereby delaying opening of mPTP. PKCɛ may stimulate ROS generation through activating mK_ATP channels, and consequentially inhibit mPTP opening. The RISK pathway also induces some other anti-apoptosis and anti-necrosis pathways. An alternative SAFE pathway recruits TNFα, which binds to TNF receptor resulting in STAT3 activation. STAT3 targets CYP-D leading to mPTP inhibition. PostC also inhibits the Na⁺/H⁺ exchanger in a PKG-dependent fashion and reduces Ca²⁺ accumulation, because the sarcolemmal Na⁺/H⁺ exchanger and the Na⁺ bicarbonate co-transporter are activated at the onset of reperfusion, which causes intracellular Ca²⁺ accumulation through reverse activation of the Na⁺/Ca²⁺ exchanger and induces cell apoptosis and necrosis. CYP-D, cyclophilin-D; eNOS, endothelial nitric oxide synthase; ERK, p42/p44 extracellular-regulated kinase; GPCR, G-protein-coupled receptor; GSK3β, glycogen synthase kinase-3β; mPTP, mitochondrial permeability transition pore; mK_ATP, mitochondrial K_ATP channel; NBC, Na⁺ bicarbonate co-transporter; NCE, Na⁺/Ca²⁺ exchanger; NHE1, Na⁺/H⁺ exchanger; NO, nitric oxide; PKCɛ, protein kinase C subtype ɛ; PKG, cGMP-dependent protein kinase; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription-3; TNFR, TNF receptor.