The predominant role of IP3 type 1 receptors in activation of store-operated Ca2+ entry in liver cells

Physiologically, hormone induced release of Ca ²⁺ from intracellular stores occurs in response to inositol 1,4,5-trisphosphate (IP ₃ ) binding to its receptors expressed on the membranes of intracellular organelles, mainly endoplasmic reticulum. These IP ₃ receptors act as channels, releasing Ca ²⁺ into the cytoplasmic space where it is responsible for regulating a host of distinct cellular processes. The depletion of intracellular Ca ²⁺ stores leads to activation of store-operated Ca ²⁺ channels on the plasma membrane which replenishes lost Ca ²⁺ and sustain Ca ²⁺ signalling. There are three isoforms of IP ₃ receptor, each exhibiting distinctive properties, however, little is known about the role of each isoform in the activation of store-operated Ca ²⁺ entry. Recent evidence suggest that at least in some cell types the endoplasmic reticulum is not a homogeneous Ca ²⁺ store, and there might be a sub-compartment specifically linked to the activation of store-operated Ca ²⁺ channels, and Ca ²⁺ release activated Ca ²⁺ (CRAC) channel in particular. Furthermore, this sub-compartment might express only certain types of IP ₃ receptor but not the others. Here we show that H4IIE liver cells express all three types of IP ₃ receptor, but only type 1 and to a lesser extent type 3, but not type 2, participate in the activation of CRAC current (I _CRAC ), while type 1 and type 2, but not type 3, participate in observed Ca ²⁺ release in response to receptor stimulation. Presented results suggest that in H4IIE rat liver cells the sub-compartment of intracellular Ca ²⁺ store linked to the activation of I _CRAC predominantly expresses type 1 IP ₃ receptors.