Astrocytic IP₃Rs: Beyond IP₃R2

Astrocytes are sensitive to ongoing neuronal/network activities and, accordingly, regulate neuronal functions (synaptic transmission, synaptic plasticity, behavior, etc.) by the context-dependent release of several gliotransmitters (e.g., glutamate, glycine, D-serine, ATP). To sense diverse input, astrocytes express a plethora of G-protein coupled receptors, which couple, via G_i/o and G_q, to the intracellular Ca²⁺ release channel IP₃-receptor (IP₃R). Indeed, manipulating astrocytic IP₃R-Ca²⁺ signaling is highly consequential at the network and behavioral level: Depleting IP₃R subtype 2 (IP₃R2) results in reduced GPCR-Ca²⁺ signaling and impaired synaptic plasticity; enhancing IP₃R-Ca²⁺ signaling affects cognitive functions such as learning and memory, sleep, and mood. However, as a result of discrepancies in the literature, the role of GPCR-IP₃R-Ca²⁺ signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IP₃R2 has been used to represent all astrocytic IP₃Rs, including IP₃R1 and IP₃R3. Indeed, IP₃R1 and IP₃R3 are unique Ca²⁺ channels in their own right; they have unique biophysical properties, often display distinct distribution, and are differentially regulated. As a result, they mediate different physiological roles to IP₃R2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca²⁺ dynamics and provide unique opportunities for integrating neuronal input and modulating astrocyte-neuron communication. The current review weighs evidence supporting the existence of multiple astrocytic-IP₃R isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca²⁺ dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IP₃R isoform.