IP3Rs

IP3 receptors (IP3Rs) are intracellular calcium release channels located on the membrane of the endoplasmic reticulum. They open in response to inositol 1,4,5-trisphosphate (IP3), a second messenger produced by phospholipase C activity following receptor or G protein-coupled receptor stimulation. IP3Rs are tetramers that can assemble as homo- or heterotetramers, enabling diverse patterns of Ca2+ signaling within the cell.

In mammals there are three functional subtypes: IP3R1, IP3R2, and IP3R3, encoded by ITPR1, ITPR2, and ITPR3. They show distinct tissue distribution and regulatory properties: IP3R1 is highly expressed in the brain, IP3R2 in several neural and glandular tissues, and IP3R3 is more ubiquitously expressed. The subunits can combine to form mixed tetramers, contributing to tissue-specific signaling behavior.

Activation of IP3Rs requires IP3 binding to the receptor's regulatory region and is modulated by cytosolic Ca2+ levels. IP3 binding induces conformational changes that open the Ca2+ pore, generating calcium-induced calcium release (CICR). Low to moderate cytosolic Ca2+ promotes channel opening, whereas high Ca2+ concentrations inhibit it. Channel activity is further regulated by ATP, Mg2+, calmodulin, and numerous interacting proteins and post-translational modifications.

Physiological roles include shaping cytosolic Ca2+ oscillations that regulate muscle contraction, secretion, neurotransmission, gene expression, development, and cell death pathways. Dysregulation of IP3R signaling has been linked to neurodegenerative and cardiovascular conditions, and mutations in ITPR1 have been associated with neurodegenerative ataxias. Pharmacological modulators such as 2-APB and xestospongins are used in research to study IP3R function.