AGE-ASSOCIATED DECREASE IN INOSITOL 1,4,5-TRISPHOSPHATE AND DIACYLGLYCEROL GENERATION BY 1,25(OH)(2)-VITAMIN-D-3 IN RAT INTESTINE

The hormonal form of vitamin D-3, 1,25 (OH)(2)-vitamin D-3( 1,25 [OH]D -2(3)), stimulates the breakdown of membrane phosphoinositides, genera ting inositol-l,di,fr-trisphosphate (IF,) and diacylglycerol (DAG) in a variety of cell systems. Several studies suggest that alterations in the receptor-mediated phosphoinositide cascade are involved in the pa thophysiology of aging. Therefore, the formation of IP3 and DAG were d etermined under basal conditions and after stimulation with physiologi cal concentrations of 1,25(OH)(2)D-3 in duodenum from young (3 mo old) and aged (24-mo-old) rats. The hormone induced a transient and biphas ic formation of IP3 and DAG. Values obtained in young rats peaking at 15 s (51% and 42% above basal levels for IP3 and DAG, respectively) an d at 3 min (90% and 74% above basal levels for IP3 and DAG, respective ly) were significantly decreased in duodenum from senescent animals (I P3: + 20% and DAG: + 18% above basal level at 15 s; and IP3: + 18% and DAG: +29% above basal level at 3 min). The 1,25(OH)(2)D-3-induced gen eration of DAG in both young and aged duodenum was effectively inhibit ed in the presence of neomycin, a phospholipase C (PLC) inhibitor, and was dependent on extracellular Ca2+. After the biphasic response, the levels of DAG generated by the hormone(10 min stimulation) remained e levated; the elevation occurred in the absence of IP3 production; and the elevated levels were not abolished by neomycin, implying that phos pholipids other than phosphoinositides are the source of DAG. This 1,2 5(OH)(2)D-3-dependent late phase of DAG generation was also diminished in aged animals. The precise molecular basis and the physiological si gnificance of decreased liberation of IP3 and DAG by 1,25(OH)(2)D-3 in the aged rat duodenum remains to be determined.