The relative order of IP3 sensitivity of types 1 and 3 IP3 receptors is pHdependent

The type-3 inositol 1,4,5-trisphosphate (IP3) receptor, in contrast to the type-1 IP3 receptor (IP3R), is not stimulated by sulfhydryl oxidation and i s less sensitive to adenosine 5'-triphosphate. In the present study we comp ared the effect of pH on the Ca2+ release induced by IP3 and cytosolic Ca2 between IP(3)R3-expressing 16HBE14o- cells and IP(3)R1-expressing A7r5 cel ls. Changing pH from 6.8 to 7.5 decreased the IP3 concentration required fo r half-maximal stimulation of IP(3)R3 (EC50) 10.7-fold (from 2.14 to 0.20 m u M). Similar alkalinization decreased the IP3 concentration (EC50) for sti mulation of IP(3)R1 only 2.5-fold (from 0.87 to 0.35 mu M). IP(3)R1 is ther efore the more sensitive isoform at pH 6.8, while IP(3)R3 is more sensitive at pH 7.5. Stimulation and inhibition of IP(3)R1 and -3 by low and high cy tosolic [Ca2+] respectively was observed at both pH 6.8 and 7.5. increasing [H+] shifted the Ca2+-activation curve of IP(3)R1 towards higher [Ca2+] bu t did not affect the Ca2+ dependence of IP(3)R3. We conclude that IP(3)R1 a nd -3 differ markedly in their response to protons.