The field of optogenetics traces its roots to the discovery of bacteriorhodopsin (BR) from Halobacterium salinarum in 1971 [1]. Subsequent studies in Xenopus oocytes demonstrated light-gated ion channel functionality of channelrhodopsin-1 (ChR1) and channelrhodopsin-2 (ChR2) through two-electrode voltage clamp measurements [2]. The term “optogenetics” was proposed in 2005, coinciding with the use of ChR2 for optical modulation of neuronal excitability [3]. These microbial rhodopsins, also known as type-1 rhodopsins, are among the earliest tools developed for light-inducible control of ion channels. In addition to microbial rhodopsins, animal rhodopsins—referred to as type-2 rhodopsins—represent another category of optogenetic tools. These are specialized G-protein-coupled receptors (GPCRs) that perceive photons to initiate G-protein- and/or arrestin-dependent signaling in eukaryotes. While microbial and animal rhodopsins share the common structure of seven transmembrane domains with a covalently bound retinal chromophore, their photochemical properties differ. Microbial rhodopsins utilize all-trans retinal (ATR), which undergoes photoisomerization to the 13-cis configuration, whereas animal rhodopsins use 11-cis retinal, isomerizing to the all-trans configuration upon photoactivation (Figure 1). Furthermore, their molecular functions vary significantly, with animal rhodopsins serving as GPCRs and photoisomerases, while microbial rhodopsins acting as ion transporters and phototaxis sensors. These unique characteristics allow rhodopsins to regulate ion transport and flux in distinct ways [4].

In addition to opsin-based tools, several opsin-free optogenetic tools have been harnessed to modulate potassium (K+) and calcium (Ca2+) channels. These tools exhibit photoinduced changes and have been applied to enable neural circuit manipulation, immunomodulation, and cardiac electrophysiology. This review provides an overview of latest progress in genetically encoded light-sensitive ion channel actuators and modulators (GELICAMs) and discusses the current challenges and future directions in this rapidly evolving field.