Encoding of Ca 2+ signals by differential expression of IP 3 receptor subtypes

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