ION CHANNELS

A remote control for switching

Calcium channels are crucial regulators of a broad range of biological processes. A photoswitchable chemical probe allows the opening and closing of these channels with unprecedented temporal resolution, providing new opportunities to study calcium-dependent signaling pathways in real time.

L-type calcium channels are essential gatekeepers that regulate how Ca2+ ions enter into cells, a process that is critical for many vital functions in our bodies such as insulin secretion or cardiac pacing. The team led by Fehrentz, Klӧcker and Trauner has developed a new chemical probe that, with the use of light only, controls whether L-type calcium channels are open or closed1. In their paper, the authors show that this small molecule works as a ‘remote control’ to switch on and off the influx of Ca2+ ions and, as a result, modulates how much insulin pancreatic cells release or how fast the heart can beat.

Photoswitches, i.e., chemical structures that change their conformation upon light irradiation, are very powerful tools for modulating chemical and biological processes2. The azobenzenes are a common type of molecular photoswitch that can interchange between cis and trans isomers by exposure to light of different wavelengths. Since a report on the formation of cis-azobenzene upon exposure to light was first described3, azobenzene photoswitches have been incorporated into numerous chemical scaffolds to generate molecules that are either active or inactive depending on the wavelength of the light they are exposed to. Using this approach, scientists have generated probes that optically control the activity of membrane receptors4 or the release of drugs in specific tissues to minimize side effects5. However, the similarity between the main L-type calcium channels Cav1.2 and Cav1.3 and other voltage-gated ion channels, such as potassium channels Kv or sodium channels Nav1.5, has hampered the design of photoswitchable probes that can reversibly regulate Ca2+ flux in a highly specific manner. Fehrentz et al.1 have chemically modified the structure of the Ca2+ channel blocker diltiazem with a hydrophilic azobenzene to create a new photoswitchable probe, termed FHU-779. Under blue illumination (470 nm) or in the dark, FHU-779 is preferentially present as the trans isomer and acts to block calcium channels. These channels are unblocked under UV irradiation (385 nm), when FHU-779 is mainly present as the cis isomer (Fig. 1). Importantly, the blockade of calcium channels by FHU-779 is reversible and therefore allows control over multiple cycles of channel switching and with full temporal resolution. This represents a significant advantage over photolytic dihydropyridine Ca2+ blockers, such as nifedipine, which can optically control Ca2+ influx but in a nonreversible manner6. Furthermore, FHU-779 has proven useful for modulating Ca2+-dependent functions of ex vivo tissues, including the release of insulin by pancreatic islets and the cardiac activity of intact hearts (Fig. 1).

Fig. 1: Optical control of calcium channels.
figure1

The diltiazem–azobenzene photoswitchable probe allows L-type calcium channels to be opened and closed, thus regulating the Ca2+ flux into cells without affecting voltage-gated potassium or sodium channels. The downstream effects of modulating the Ca2+ flux were validated in intact tissues by optical control of insulin release in pancreatic islets and cardiac activity in ex vivo explanted hearts. c, cis; t, trans.

The activity of L-type calcium channels is associated with multiple tissues (for example, brain, heart, smooth muscle, retina, and pancreas) and biological processes beyond insulin secretion and heart pacing. Therefore, the possibility of regulating Ca2+ influx in a noninvasive and reversible manner opens a whole range of exciting opportunities to design experimental models to understand the role(s) of Ca2+ movement through channels in healthy and disease states. Given the direct links to cardiovascular and metabolic diseases, this could be the first step toward photoresponsive biomaterials that may be combined with miniaturized implants7 as therapeutic or monitoring devices. In the near future, we will see this technology being applied not only to ex vivo tissues or organs, such as pancreatic islets or intact hearts, but also in vivo in whole intact organisms, in which intercellular networks are maintained so that the broader implications of Ca2+ flux can be better understood. For instance, zebrafish, which are optically transparent organisms and therefore fully compatible with the use of visible light8, could be excellent models to assess how photoactivatable chemical tools modulate cellular function in vivo.

Expanding the chemical toolbox to include longer wavelengths with deeper tissue penetration (or even better, toward a multi-color palette of photoresponsive tools) may create avenues to remotely control multiple voltage-gated ion channels at the same time. To this end, recent chemical advances in molecular photoswitches that respond to light of different colors (including near-infrared light9) will pave the way for multiplexed systems in which different signal transduction pathways may be turned on and off at will, with the precision of light. At the end of the day, there are few things easier to operate than a light switch.

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Correspondence to Marc Vendrell.

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Vendrell, M. A remote control for switching. Nat Chem Biol 14, 749–750 (2018). https://doi.org/10.1038/s41589-018-0107-3

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