• Advancing Drug Discovery with Electrophysiological Tools for Lysosomal and Organellar Ion Channels

A recent perspective by Niels Fertig and Alexandre Santinho outlines how recent innovations in automated patch clamp (APC) and solid-supported membrane electrophysiology (SSME) are reshaping access to intracellular ion channels. These technologies, adapted for use on purified organelles, allow direct electrophysiological recordings from native lysosomal membranes without requiring artificial swelling or overexpression.

The publication focuses on two lysosomal targets of growing pharmaceutical interest: TMEM175, a K⁺/H⁺ leak channel implicated in Parkinson’s disease, and TRPML1, a Ca²⁺ channel involved in lysosomal trafficking and autophagy. Both are now accessible for high-throughput pharmacological profiling using tools like Lysopatch and commercial SSME platforms.

The review further notes a marked increase in industry engagement, citing a 25% annual growth in patent activity targeting lysosomal ion channels between 2010 and 2020. Several emerging biotech firms (e.g., Lysoway, Tenvie, Threebrooks) have aligned their pipelines around small-molecule modulators of these intracellular targets.

This work underscores a broader shift: from plasma membrane-centric drug discovery to intracellular ion channels as legitimate, druggable targets, made feasible by scalable electrophysiological technologies.

• Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches

In a comprehensive review, Kondratskyi et al. summarize recent progress in the functional and structural characterization of lysosomal ion channels and transporters, with a focus on their disease relevance and therapeutic potential.

The review examines more than a dozen targets—including TRPML1, TMEM175, TPC2, CLN7, and P2X4—each discussed in terms of ion selectivity, regulatory mechanisms, and physiological roles. Several lesser-known but promising candidates are also highlighted, such as TMEM165, a recently identified Ca²⁺ importer activated by luminal acidification, and SLC17A9 (VNUT), an ATP transporter with emerging links to neuroinflammation and pain.

Technological advances are also central to this work. The authors emphasize how cryo-electron microscopy, APC, SSME, and fluorescent biosensors now allow multi-modal study of ion flux, membrane potential, and transporter kinetics directly in lysosomal preparations.

Overall, the review positions lysosomal ion channels as key molecular mediators of autophagy, lysosomal trafficking, pH balance, and immune signaling, underscoring their value as both biological probes and therapeutic targets in neurodegenerative and metabolic disease.

• Recent Developments in Probing Organellar Ion Flux and Mechanosensitivity

A methodological review by Taufiq Rahman and Sandip Patel details new tools for probing ionic flux and mechanosensitivity across endomembranes, with a strong focus on functional readouts in intact organelles.

The study introduces solid-supported membrane electrophysiology (SSME) as an enabling technology for transporters and low-turnover channels that are otherwise difficult to assess. TMEM175 and PHT1 are cited as successful examples where SSME provided clear current profiles from native vesicle preparations.

The paper also presents a new generation of DNA-based nanodevices, pHlicKer (for K⁺) and RatiNa (for Na⁺), which allow researchers to image organellar ion concentrations in situ, even within live cells or model organisms. These ratiometric tools offer FRET-based precision and organelle-specific targeting motifs, supporting measurements in structures such as lysosomes, endosomes, and the Golgi.

Additionally, the authors highlight optogenetic approaches such as LIMER, a light-inducible system for ER deformation, which enables targeted activation of mechanosensitive channels like TRPV1 and PKD2 in response to mechanical stress.

Together, these techniques redefine what is experimentally accessible within organelles, expanding electrophysiology beyond traditional membranes and allowing simultaneous study of transport, signaling, and mechanotransduction in a native context.