Astrocytic IP(3)Rs: Beyond IP(3)R2

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 Ca(2+) release channel IP(3)-receptor (IP(3)R). Indeed, manipulating astrocytic IP(3)R-Ca(2+) signaling is highly consequential at the network and behavioral level: Depleting IP(3)R subtype 2 (IP(3)R2) results in reduced GPCR-Ca(2+) signaling and impaired synaptic plasticity; enhancing IP(3)R-Ca(2+) 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-IP(3)R-Ca(2+) signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IP(3)R2 has been used to represent all astrocytic IP(3)Rs, including IP(3)R1 and IP(3)R3. Indeed, IP(3)R1 and IP(3)R3 are unique Ca(2+) 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 IP(3)R2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca(2+) 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-IP(3)R isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca(2+) dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IP(3)R isoform.