Co-expression of prostaglandin receptors with opposite effects: a model for homeostatic control of autocrine and paracrine signaling.
Prostaglandins are ubiquitous autocrine mediators that exert their effects through a number of G protein-coupled receptors. Many organs and tissues express many of the prostaglandin receptors, and prostaglandins have diverse effects on individual organs and tissues. In some cases, several prostaglandin receptors are expressed on a single cell type. Co-expressed prostaglandin receptors frequently appear to have opposite actions, suggesting homeostatic control of prostaglandin effects. Co-expression of opposing receptors provides a molecular mechanism for weak or partial agonism and explains the action of a drug as a mixed agonist/antagonist. The physiological relevance of co-expressed opposing receptors for a single agonist perhaps can be explained in terms of the difference between endocrine and autocrine mediators. Endocrine hormones are generally produced by cells distant from their site of action so that they are diluted to an elevated but stable concentration by the time they reach their target cells. In contrast, autocoids are produced by the same cell type on which they act and may reach transiently high levels at their sites of action. The presence of a second type of receptor that negates the action of the first receptor would tend to buffer cellular responses to transient extremes of agonist concentration. The slow onset of inhibition would also allow for time-dependent buffering, providing additional control over autocoid release and effect. The mechanism is relevant to other autocrine and paracrine mediators including neurotransmitters, which reach transiently high concentrations in the synaptic cleft.
Ashby
B
B
Department of Pharmacology, Temple University Health Sciences Center, Philadelphia, PA 19140, USA. bashby00@nimbus.ocis.temple.edu
D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D011485:Protein Binding; D011982:Receptors, Prostaglandin / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
D011982:Receptors, Prostaglandin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins