The capacity for the neurotrophic factor PACAP38 to regulate expression of nerve growth factor (NGF)-trkA receptors in PC12 cells has been examined. Treatment of PC12 cells with 5 nM PACAP38 for 48 h elicited a 2.5-fold increase in 125I-NGF binding sites. FACS and Western analysis of trkA receptor protein indicate an abundance of receptors. The PACAP38-selective antagonist PACAP 6-38 blocked trkA receptor upregulation elicited by PACAP38. The expression of epidermal growth factor receptors was not affected by PACAP38 suggesting that upregulation of trkA represents a selective effect of this neurotrophic peptide. Similarly, expression of the pan-neurotrophin binding receptor p75 was not altered by PACAP38 treatment. In addition to effects on trkA observed in wild-type PC12 cells, PACAP38 stimulated an increase in the level of expressed human trkA receptors stably transfected into PC12 cells. PACAP38 provoked an increase in basal and NGF-stimulated phosphorylation of trkA. Enhanced phosphorylation of trkA was detected as early as 6 h following addition of PACAP38 and was maximal at 48 h. Increased incorporation of phosphate occurs on both serine and tyrosine residues of trkA. These results suggest that PACAP38 is able to promote upregulation of trkA receptors, an event associated with elevated serine/tyrosine phosphorylation of trkA.