Regulatory role of retinoic acid on cultured mouse keratinocyte inositol phospholipid metabolism: dose-dependent release of inositol triphosphate.
The incorporation of precursor 14C-myoinositol into the three cellular inositol phospholipids (PtdIns, PtdInsP, and PtdInsP2) of cultured, rapidly proliferating keratinocytes is significantly enhanced by the exogenous addition of a high concentration (1 X 10(-7) M) of all-trans retinoic acid or its analog 13-Cis analog, whereas a similar incubation with a low concentration (1 X 10(-10) M) of the same retinoid resulted in an insignificant incorporation of the radio-precursor into the three inositol phospholipids. Incorporation was most marked into the more phosphorylated PtdIns4P and PtdIns4,5P2. These results indicate that retinoic acid affects the biosynthesis of the inositol phospholipids at high concentrations. In contrast, the hydrolysis of 14C-PtdIns4,5P2 and release of 14C-InsP3 from the prelabeled keratinocytes is markedly enhanced by a low physiologic concentration (1 X 10(-10) M) of retinoic acid or its 13-Cis analog. The hydrolysis is rapid, with an accompanying elevated transient release of 14C-InsP3. High concentration (1 X 10(-5) M), on the other hand, supresses 14C-InsP3 release. These results taken together underscore a bifunctional, dose-dependent effect of both the all-trans-RA and its 13-Cis analog on the synthesis and hydrolysis of keratinocyte PtdIns4,5P2. Furthermore, the results suggest that at low physiologic concentrations, these retinoids may function as agonists to perturb the membrane resulting in induced rapid hydrolysis of cellular PtdIns4,5P2, which is coupled to a "transient" generation of InsP3 (an intracellular second messenger). The rapid formation of this putative "second messenger" may in turn play a role in the cellular proliferative or differentiating biochemical events in the murine keratinocytes.
Tang
W
W
Department of Dermatology, School of Medicine, University of California, Davis 95616.
Ziboh
V A
VA
Isseroff
R
R
Martinez
D
D
D000818:Animals; D002478:Cells, Cultured; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D006868:Hydrolysis; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism*; D007633:Keratins; D051379:Mice; D008807:Mice, Inbred BALB C; D010716:Phosphatidylinositols / Q000096:biosynthesis / Q000378:metabolism*; D013237:Stereoisomerism; D013403:Sugar Phosphates / Q000378:metabolism*; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D013403:Sugar Phosphates; D014212:Tretinoin; D007633:Keratins; D015544:Inositol 1,4,5-Trisphosphate