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

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 is less sensitive to adenosine 5'-triphosphate. In the present study we compared 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 cells. Changing pH from 6.8 to 7.5 decreased the IP3 concentration required for half-maximal stimulation of IP(3)R3 (EC50) 10.7-fold (from 2.14 to 0.20 mu M). Similar alkalinization decreased the IP3 concentration (EC50) for stimulation of IP(3)R1 only 2.5-fold (from 0.87 to 0.35 mu M). IP(3)R1 is therefore 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 cytosolic [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+] but did not affect the Ca2+ dependence of IP(3)R3. We conclude that IP(3)R1 and -3 differ markedly in their response to protons.