Abstract

Inositol 1,4,5-trisphosphate (IP₃) plays a key role in Ca²⁺ signalling, which exhibits a variety of spatio-temporal patterns that control important cell functions. Multiple subtypes of IP₃ receptors (IP₃R-1, -2 and -3) are expressed in a tissue- and development-specific manner and form heterotetrameric channels through which stored Ca²⁺ is released, but the physiological significance of the differential expression of IP₃R subtypes is not known. We have studied the Ca²⁺-signalling mechanism in genetically engineered B cells that express either a single or a combination of IP₃R subtypes, and show that Ca²⁺-signalling patterns depend on the IP₃R subtypes, which differ significantly in their response to agonists, i.e. IP₃, Ca²⁺ and ATP. IP₃R-2 is the most sensitive to IP₃ and is required for the long lasting, regular Ca²⁺ oscillations that occur upon activation of B-cell receptors. IP₃R-1 is highly sensitive to ATP and mediates less regular Ca²⁺ oscillations. IP₃R-3 is the least sensitive to IP₃ and Ca²⁺, and tends to generate monophasic Ca²⁺ transients. Furthermore, we show for the first time functional interactions between coexpressed subtypes. Our results demonstrate that differential expression of IP₃R subtypes helps to encode IP₃-mediated Ca²⁺ signalling.