IP sub(3) receptor purified from liver plasma membrane is an (1,4,5)IP sub(3) activated and (1,3,4,5)IP sub(4) inhibited calcium permeable ion channel

The IP sub(3) receptor is involved in Ca super(2+) mobilization from intracellular stores. Recently, we purified an inositol (1,4,5)-trisphosphate receptor from rat liver plasma membrane (LPM-IP sub(3)R). The purified LPM-IP sub(3) receptor was incorporated into vesicle derived planar bilayers and its channel properties characterized. The receptor displayed ion channel activity that was activated by inositol (1,4,5)-trisphosphate [(1,4,5)IP sub(3)] (1 mu M) and inhibited by inositol (1,3,4,5)-tetrakisphosphate (IC sub(50) similar to 1 mu M) and by heparin (IC sub(50) similar to 20 mu g/ml). The channel displays a unitary conductance of 9 pS, and 13 pS in symmetrical 100 mM and 500 mM KCl, respectively, and in symmetrical 250 mM cesium methanesulfonate the slope conductance is 11 pS. Activation by (1,4,5)IP sub(3) is specific to the cis-side of the chamber, equivalent to the cytoplasmic face. The receptor is a Ca super(2+) permeable ion channel based on ion selectivity (Ca super(2+) > K super(+) > Na super(+) >> Cl super(-)). The LPM-IP sub(3) receptor was also permeable to Cs (Cs super(+) greater than or equal to K super(+)), similar to other intracellular Ca super(2+) release channels, i.e. the IP sub(3) receptor from brain and smooth muscle (IP sub(3)R-1) and the ryanodine receptor from skeletal muscle (RyR-1) and heart (RyR-2). Channel activity is not voltage dependent ( plus or minus 100 mV applied voltage). The channel is activated by ATP and Ca super(2+). The open probability of the (1,4,5)IP sub(3) activated channel activity displays a bell shaped response to cis Ca super(2+) ion concentration of our system. The LPM-IP sub(3) receptor differs from intracellular IP sub(3)R-1 in that the Ca super(2+) and ATP concentration required for maximum activation is about 10 times higher as compared with IP sub(3)R-1 from brain cerebellum and smooth muscle. We conclude that the LPM-IP sub(3) receptor is an (1,4,5)IP sub(3) activated Ca super(2+) permeable ion channel. The implication of our studies is that in liver, (1,4,5)IP sub(3) regulates Ca super(2+) influx via the plasma membrane.