University of Giessen Lung Center

Prostanoid signaling

Prostacyclin (PGI2) is the major product of cyclooxygenases (COX) in the vascular endothelium and mediates potent anti-platelet, vasodilator, and anti-inflammatory actions by a prostacyclin receptor (IP). This receptor is a member of the G protein-coupled receptor (GPCR) superfamily and is coupled to adenylate cyclase (AC) and phospholipase C (PLC). The prostanoid receptors are classified into DP, IP, EP (EP 1-4), FP and TP receptors with different affinities for agonists and different roles in signal transduction. The IP, EP2, EP4 and DP receptors are coupled to stimulation of adenylate cyclase, while the TP, EP1 and FP receptors are coupled to Ca2+ mobilization. The EP3 receptor is an alternative spliced gene, with at least 8 isoforms identified so far. Depending on the subtype, this receptor can be negatively of positively coupled to Gs. Agonist-binding to the IP receptor leads to activation of protein kinase A by cyclic adenosine monophosphate (cAMP). Disturbances to prostacyclin synthesis, as well as polymorphisms of the PGI2-synthase (PGIS), have been linked to severe pulmonary hypertension. Substitution of prostacyclin, either by overexpression of the PGIS in an experimental model or by application of PGI2 or its analogs iloprost or beraprost in patients decreases pulmonary artery pressure. However, tolerance of the lung vasodilatory response to continuously infused prostacyclin rapidly develops in patients with severe pulmonary hypertension, and dose adjustments have to be made. In COPD patients with pulmonary hypertension, the pulmonary vasodilatory response to continuously infused prostacyclin was found to dissipate within 24 h. Marked tolerance to the antimitogenic actions of prostacyclin developed within 24 h in coronary artery smooth muscle cells. Basic studies demonstrated that desensitization of the IP receptor occurs within minutes after exposure to agonists and is due to agonist-induced receptor phosphorylation, mainly mediated by PKC, with subsequent sequestration of the intact receptor and removal from the cell surface. In addition, there is evidence for changes in adenylate cyclase and phosphodiesterase activation occurring in response to IP receptor stimulation, which may contribute to loss of the vasodilatory response to prostacyclin and its analogues.