|Budget Amount *help
¥2,600,000 (Direct Cost : ¥2,600,000)
Fiscal Year 1996 : ¥1,100,000 (Direct Cost : ¥1,100,000)
Fiscal Year 1995 : ¥1,500,000 (Direct Cost : ¥1,500,000)
We previously identified three isoforms of the mouse prostaglandin (PG) E receptor EP3 subtype, EP3alpha, EP3beta and EP3gamma, with different COOH-terminal tails, produced through alternative splicing. We examined the Gi activities of these isoforms. The EP3alpha receptor showed marked agonist-independent constitutive Gi activity, the EP3beta receptor had no constitutive activity, and the EP3gamma receptor showed mostly full constitutive activity. Thus, the EP3 receptor isoforms differ in constitutive Gi activity.
Among four PGE receptor subtypes, the EP2 and EP4 receptors are coupled to the same signal transduction pathway, stimulation of adenylate cyclase. However, the EP4 receptor underwent short term agonist-induced desensitization, but no such desensitization was observed for the EP2 receptor. On the other hand, PGE_2 is rapidly metabolized to 15-keto-PGE_2. The EP4 receptor markedly lost the response for the metabolite, but the EP2 receptor still had significant response. Therefore, the physiological significance of EP2 and EP4 receptors may lie in their different sensitivities to agonist-induced short term desensitization and their differential susceptibilities to the metabolic inactivation of the agonist.
The EP3 receptor is widely distributed in the nervous system and is specifically localized to neurons. when the EP3 receptor was expressed in PC-12 cells, in the differentiated cells, an EP3 agonist caused neurite retraction in a pertussis toxin-insensitive manner. C3 exoenzyme completely inhibited the EP3 agonist-induced neurite retraction when microinjected into the cells, indicating that the morphological effect of the EP3 receptor is dependent on Rho activity.