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Homologous desensitization of ATP‐stimulated mitogenesis: Mechanism involves desensitization of arachidonic acid release and cAMP elevation but not the activation of protein kinase A
Author(s) -
Huang NingNa,
Wang DingJi,
Heller Elizabeth,
Heppel Leon A.
Publication year - 1995
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1041650326
Subject(s) - homologous desensitization , desensitization (medicine) , cycloheximide , biology , dna synthesis , protein kinase c , protein kinase a , arachidonic acid , adenylyl cyclase , phospholipase a2 , endocrinology , stimulation , medicine , receptor , biochemistry , kinase , protein biosynthesis , enzyme , dna
Prolonged incubation of quiescent 3T3, 3T6, and A431 cells with the P 2Y purinoceptor agonists ATP, ADP, or AMPPNP reduced the mitogenic responses of target cells to a further challenge by these agonists, as measured by [ 3 H]thymidine incorporation. The mitogenic desensitization was agonist‐specific, for no effect was seen on DNA synthesis stimulated by epidermal growth factor, insulin, bombesin, 12‐0‐tetradecanoyl‐phorbol‐12 acetate (TPA), or adenosine. The desensitization was completely reversible, since after a 24 hr incubation in the absence of ATP, the cells responded fully to the mitogenic action of ATP. The presence of a low level of cycloheximide blocked recovery, suggesting that down‐regulation of the P 2Y receptor may have occurred during desensitization. In Swiss 3T3 cells, stimulation of DNA synthesis occurs predominantly by activation of arachidonic acid release, followed by its oxidation to prostaglandin E 2 and stimulation of adenylyl cyclase. Interestingly, prolonged preincubation with ATP produced a similar degree of desensitization of DNA synthesis and of ATP‐dependent arachidonic acid release and cAMP accumulation. Furthermore, this was true for both wild type cells and mutants with a defective cAMP‐dependent protein kinase (PKA). We conclude that homologous desensitization is likely due to uncoupling of the P 2Y purinoceptor from phospholipase A 2 , and this process does not require activation of protein kinase A. © 1995 Wiley‐Liss Inc.