FUNCTIONAL DESENSITIZATION DUE TO STIMULATION OF CYCLIC AMP-PHOSPHODIESTERASE IN HUMAN MONONUCLEAR LEUKOCYTES

  • 1 January 1982
    • journal article
    • research article
    • Vol. 8  (4) , 211-224
Abstract
Heterologous desensitization of human mononuclear leukocytes (MNL) by incubation of low (e.g., 10-6 M) concentrations of histamine, isoproterenol and prostaglandin E1 has been demonstrated. Subsequent exposure of the cells to stimulating (e.g., 10-3-10-5 M) responses. Possible mechanisms for the subnormal responsiveness include rapid degradation of cAMP. Time-dependent elevation of cAMP-phosphodiesterase (PDE) activity was demonstrated following agonist desensitization. The increased enzyme activity was accompanied by a mirror-image decrease in cAMP responsiveness. The effect was rapid and prolonged with recovery time proportional to desensitization time. Cycloheximide failed to inhibit the increase of cAMP-PDE activity caused by short-term histamine exposure, but partially diminished the elevation as the result of chronic histamine desensitization. Three different kinetic forms of cAMP-PDE were observed in MNL, designated as I, II and III, each with distinctive Km and Vmax. Histamine desensitization increased the activity of form II and drastically reduced that of form I. A possible conversion of lymphocyte cAMP-PDE from form I to the form II more characteristic of monocytes was observed. Agonist-induced increases in cAMP-PDE activity and changes in enzyme kinetic characteristics represent a potentially important mechanism of functional desensitization. This may have significant effects on biological regulation of cyclic nucleotides.