TABLE 2.

Genetically encoded actuators for interrogating astrocyte function^a

Available actuators for astrocyte “excitation”
Actuator type	Actuator name(s)	Mechanism	References
Calcium	ChR2, CatCh	Cation channel	Beppu et al., 2014; Figueiredo et al., 2014
	ArchT	Proton pump	Beppu et al., 2014; Poskanzer & Yuste, 2016
	Opto-XRs	G-protein signalingb	Figueiredo et al., 2014
	DREADDs	G-protein signalingb	Chai et al., 2017; Durkee et al., 2019
cAMP/cGMP	YFP-CaRhAC/YFP-CaRhGC	Enzyme activity (adenylyl/guanylyl cyclase)	Scheib et al., 2018
Available actuators for astrocyte “inhibition”
Actuator type	Actuator name(s)	Mechanism	References
Calcium	CalEx	Reduces calcium signaling after expression of the plasma membrane calcium pump PMCA2	Yu et al., 2018; Yu et al., 2021
	SpiCee	Reduces calcium signaling by calcium binding to a chimeric calmodulin- and ɑ-parvalbumin-based calcium buffer	Ros et al., 2020
	iβARK	Attenuates Gq-GPCR-evoked calcium signaling by sequestering Gɑq-GTP	Nagai, Bellafard, et al., 2021
cGMP	SponGee	Reduces cGMP signaling by cGMP binding to a chimeric PKG1ɑ/PKG1β cGMP buffer	Ros et al., 2019
IP3	IP3 sponge	Competes with the endogenous IP3Rs for IP3 binding in a dose-dependent manner	Miyamoto & Mikoshiba, 2017; Uchiyama et al., 2002

Abbreviations: cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; GPCR, G-protein coupled receptor; IP₃, inositol-trisphosphate.

^aWhile these actuators may target a specific signaling pathway, it is important to note that their effects can be broad, indirect, and divergent. For example, CalEx expression leads to numerous gene expression changes affecting multiple astrocyte functions at once (Nagai, Bellafard, et al., 2021). ChR2 and ArchT both elevate intracellular calcium levels but have opposing effects on glutamate release (Beppu et al., 2014). Calcium elevations can be partly due to autocrine signaling following stimulated transmitter release (e.g., ATP) (Figueiredo et al., 2014).

^bUnlike in neurons, “inhibitory” opsins and DREADDs typically lead to calcium excitation in astrocytes (Durkee et al., 2019; Poskanzer & Yuste, 2016).