The effects of protein kinase A (PKA) on the inositol 1,4,5-trisphosphate (InSP3) receptor isoforms type I and type III were studied. The effects of PKA on the extent and rate constants for InSP3-induced Ca2+ release (IICR) were different for the two isoforms. The effects of PKA on the type I isoform showed a biphasic relationship dependent upon the concentration of PKA used. At low concentrations of PKA (<50 U/ml), both the extent and rate constants for IICR increased, while at higher concentrations (>200 U/ml) the extent and rate constants decreased. The type III isoform showed only an increase in the extent of IICR and not in the rate constants. The effects of PKA on the type I InSP3 receptor using single channel electrophysiological studies were also investigated. The stimulatory effect of PKA is due to an increase in conductance levels and not to a change in the mean open time of the channel. (C) 2003 Elsevier Science (USA). All rights reserved.