Short-term desensitization of prostaglandin F2α receptors increases cyclic AMP formation and reduces inositol phosphates accumulation and contraction in the bovine iris sphincter

Abstract

The effect of short-term prostaglandin (PG) desensitization on PGF2 alpha receptor-mediated inositol phosphates accumulation, 1,2-diacylglycerol production, measured as phosphatidic acid (PA), myosin light chain (MLC) phosphorylation, cAMP formation and contraction was investigated in bovine iris sphincter smooth muscle. We have found that incubation of the sphincter with 25 microM PGF2 alpha for 45 min leads to: (a) significant loss in sensitivity of the tissue to PGF2 alpha receptor-stimulated inositol phosphates accumulation, PA production, MLC phosphorylation and contraction, and (b) significant increase in both basal and PGF2 alpha-stimulated cAMP formation. These changes are probably not due to reduction in phospholipid synthesis because there were no detectable differences in basal phospholipid labeling, either from 3H-inositol or from 32P, between normal and desensitized muscles. Preincubation of the sphincter in the absence of PGF2 alpha for 45 min did not lead to alterations in the biochemical-pharmacological responsiveness of the control muscle to PGF2 alpha. Our results suggest that desensitization of PG receptors in the iris sphincter occurs by a receptor-specific process. The PG receptor mediating contraction (IP3-Ca2+) is selectively susceptible to desensitization, in contrast with the receptor mediating smooth muscle relaxation (cAMP). These findings add further support to the developing hypothesis that there are functional and biochemical reciprocal interactions between the IP3-Ca2+ and cAMP messenger systems in the iris of the mammalian eye.