Encoding of Ca2+ signals by differential expression of IP3 receptor subtypes

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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.