Photocontrolling Microtubule Dynamics with Photoswitchable Chemical Reagents

Thorn‐Seshold, Oliver; Meiring, Joyce

doi:10.1007/978-1-0716-1983-4_26

Cited by 9 publications

(2 citation statements)

References 32 publications

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“…However, due to the typically 20% residual Z isomer in the mostly-E-PSS, even an ideal affinity switch that has a completely non-binding E-isomer but a high-agonistpotency Z-isomer (Figure 1e) suffers substantial background activity after Z→E photo-switching-off. Conceptually, this is covered in the general result that bidirectional photocontrol of an affinity switch can only deliver a narrow functional dynamic range of bioactivity (FDR), 38,39 i.e. the bioactivity window between best-photoswitched-on and best-photo-switched-off states (Figure 1f; the FDR is limited by its PSSs in both directions).…”

Section: Resultsmentioning

confidence: 99%

Ideal efficacy photoswitches for TRPC4/5 channels harness high potency for spatiotemporally-resolved control of TRPC function in live tissues

Müller,

Niemeyer,

Ojha

et al. 2024

Preprint

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Directly probing the endogenous biological roles of target proteins with high spatial and temporal resolution, as non-invasively and reproducibly as possible, is a shared conceptual goal for research across many fields, as well as for targeted therapies. Here we describe the rational conceptual design and test-case practical implementation of a photopharmacological paradigm to empower high-performance photomodulation studiesin vivo. TRPC4/5 ion channels are involved in many spatiotemporally resolved circuits, from pain and anxiety, to reproductive signaling, digestion, and obesity. To unpick their biology requires spatiotemporally precise tools, which were lacking. We developed “ideal efficacy photoswitch” ligands to control their diverse functionsin situ. TheseE⇆Z-photoswitchable ligands bias TRPC[4]/5 channel activity with exquisite photocontrol, from strong agonism under 360 nm, to low agonism at 385 nm, to strong antagonism at 410-460 nm. Cryo-EM structures of both TRPC4 and TRPC5 with bothZ-agonists andE-antagonists support the rationale for efficacy switching through competitiveE/Zisomer binding. Crucially, since theE/Zratio is exclusively determined by the light wavelength applied,their channel photocontrol is exclusively wavelength-dependent, yet drug-concentration-independent: so is reproducible from cell culture to >millimetre-depth tissues. Indeed, we were able to photocontrol both direct and downstream TRPC4/5 biology in cell lines or primary cells in culture, from calcium flux, to primary neuron excitability and adrenaline release; and even in tissues, photoswitching small intestine motility and peristalsis. The TRPC4/5 ligands we develop will thus unlock a range of high-precision investigations in TRP biology. More broadly, we propose that the success of this efficacy photoswitch program, from concept to tissue level translation, is mainly a consequence of how biology has evolved proteins for efficacy control. We therefore foresee that a variety of functionally responsive protein targets, not only sensory and signaling ion channels and receptors, will be amenable to similarly high-performance photocontrol evenin vivo, if a new generation of reagent development adopts this paradigm ofideal efficacy photoswitching.Table of Contents Graphic

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Section: Resultsmentioning

confidence: 99%

Ideal efficacy photoswitches for TRPC4/5 channels harness high potency for spatiotemporally-resolved control of TRPC function in live tissues

Müller,

Niemeyer,

Ojha

et al. 2024

Preprint

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“…6 Developing spatiotemporally-targetable MT modulators has thus been an important goal, and optical control strategies have been prioritised since light can be applied with high spatiotemporal precision even in vivo. 7,8 Although a few optogenetic MT-modulating tools were recently created, [9][10][11] most research has focused on chemical tools. Irreversibly photobleachable or photouncageable inhibitors were the rst developed; these were followed by tools using C]C double bond photoisomerisation that is irreversible in practice.…”

Section: Mt Biology Needs Spatiotemporally Precise Reagentsmentioning

confidence: 99%

A photo-SAR study of photoswitchable azobenzene tubulin-inhibiting antimitotics identifying a general method for near-quantitative photocontrol

Reynders,

Garścia,

Müller-Deku

et al. 2024

Chem. Sci.

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BTDAzo: A Photoswitchable TRPC5 Channel Activator**

et al. 2022

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Photoswitchable reagents can be powerful tools for high-precision biological control. TRPC5 is a Ca 2 + -permeable cation channel with distinct tissuespecific roles, from synaptic function to hormone regulation. Reagents giving spatiotemporally-resolved control over TRPC5 activity may be key to understanding and harnessing its biology. Here we develop the first photoswitchable TRPC5-modulator, BTDAzo, to address this goal. BTDAzo can photocontrol TRPC5 currents in cell culture, as well as controlling endogenous TRPC5-based neuronal Ca 2 + responses in mouse brain slices. BTDAzos are also the first reported azobenzothiadiazines, an accessible and conveniently derivatised azoheteroarene with strong two-colour photoswitching. BTDAzo's ability to control TRPC5 across relevant channel biology settings makes it suitable for a range of dynamically reversible photoswitching studies in TRP channel biology, with the aim to decipher the various biological roles of this centrally important ion channel.

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Photocontrolling Microtubule Dynamics with Photoswitchable Chemical Reagents

Cited by 9 publications

References 32 publications

Ideal efficacy photoswitches for TRPC4/5 channels harness high potency for spatiotemporally-resolved control of TRPC function in live tissues

Ideal efficacy photoswitches for TRPC4/5 channels harness high potency for spatiotemporally-resolved control of TRPC function in live tissues

A photo-SAR study of photoswitchable azobenzene tubulin-inhibiting antimitotics identifying a general method for near-quantitative photocontrol

BTDAzo: A Photoswitchable TRPC5 Channel Activator**

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