Signaling by Eicosanoids

Eicosanoids signal via activation of 7-transmembrane domain G protein-coupled receptors (GPCRs). These are a diverse family of receptors that also includes chemokine and lysophospholipid receptors. Receptors for eicosanoids include EP (PGE2), IP (prostacyclin), TP (thromboxane), CysLT1/T2 (leukotrienes) and ALX (lipoxin).

Essential roles for signaling via GPCRs have been revealed using knockout and transgenic mice. For example IP_/~ mice have demonstrated important roles for prostacyclin via this pathway in vascular homeostasis [18,19]. In particular, the mice are more susceptible to thrombosis, intimal hyperplasia, atherosclerosis, restenosis and reperfusion injury. Naturally occurring mutations in the human IP have begun to provide insight into the proposed cardioprotective role of this pathway [20]. In the case of EP/PGE2, the EP4 isoform appears to be important in osteogenesis and may play important roles in rheumatoid arthritis [21]. Finally, the PGD2 receptors DP1 and CRTH2 have been proposed as therapeutic targets in allergic diseases [22].

GPCRs activated by eicosanoids can mediate opposing effects in the same system. For example, COX-2-derived PGI2 signaling via IP causes smooth muscle relaxation and inhibits platelet aggregation. In contrast, COX-1-generated thromboxane A2 (TXA2) is a potent platelet activator and stimulates smooth muscle constriction, via the thromboxane receptor (TP) (Figure 10.10). These opposing effects need to be kept in balance in the vasculature, and have led to the concept of maintaining a prosta-glandin/thromboxane ratio for regulating vascular homeostasis [23]. The importance of this has been recently highlighted by the observations of elevated risk of cardiovascular events in patients prescribed selective COX-2 inhibitors, where inhibition of PGI2 - but not TX - may contribute to thrombosis and elevated blood pressure.

Separate to signaling via GPCRs, some eicosanoids can mediate signaling by nuclear receptors/transcription factors, for example the peroxisomal proliferator

I 10 Eicosanoid-Based Signaling Platelets

Endothelium/vessel wall

collagen, thrombin, ADP

shear, bradykinin, acetylcholine

Was this article helpful?

0 0
Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

Get My Free Ebook

Post a comment