Small molecule inhibits KCNQ channels with a non-blocking mechanism
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Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome
A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of “interactome mapping” and illustrate by example the multiple protein–protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.
Theoretical analysis of low-power deep synergistic sono-optogenetic excitation of neurons by co-expressing light-sensitive and mechano-sensitive ion-channels
The present challenge in neuroscience is to non-invasively exercise low-power and high-fidelity control of neurons situated deep inside the brain. Although, two-photon optogenetic excitation can activate neurons to millimeter depth with sub-cellular specificity and millisecond temporal resolution, it can also cause heating of the targeted tissue. On the other hand, sonogenetics can non-invasively modulate the cellular activity of neurons expressed with mechano-sensitive proteins in deeper areas of the brain with less spatial selectivity. We present a theoretical analysis of a synergistic sono-optogenetic method to overcome these limitations by co-expressing a mechano-sensitive (MscL-I92L) ion-channel with a light-sensitive (CoChR/ChroME2s/ChRmine) ion-channel in hippocampal neurons. It is shown that in the presence of low-amplitude subthreshold ultrasound pulses, the two-photon excitation threshold for neural spiking reduces drastically by 73% with MscL-I92L-CoChR (0.021 mW/µm2), 66% with MscL-I92L-ChroME2s (0.029 mW/µm2), and 64% with MscL-I92L-ChRmine (0.013 mW/µm2) at 5 Hz. It allows deeper excitation of up to 1.2 cm with MscL-I92L-ChRmine combination. The method is useful to design new experiments for low-power deep excitation of neurons and multimodal neuroprosthetic devices and circuits.
Decoding the mechanism of proanthocyanidins in central analgesia: redox regulation and KCNK3 blockade
Neuropathic pain causes enduring physical discomfort and emotional distress. Conventional pharmacological treatments often provide restricted relief and may result in undesirable side effects, posing a substantial clinical challenge. Peripheral and spinal redox homeostasis plays an important role in pain processing and perception. However, the roles of oxidative stress and antioxidants in pain and analgesia on the cortical region during chronic pain remains obscure. Here we focus on the ventrolateral orbital cortex (VLO), a brain region associated with pain severity and involved in pain inhibition. Using a spared nerve injury mouse model, we observed the notable reactive oxygen species (ROS)-mediated suppression of the excitability of pyramidal cells (PYRVLO) in the VLO. Nasal application or microinjection of the natural antioxidants proanthocyanidins (PACs) to the VLO specifically increased the activity of PYRVLO and induced a significant analgesic effect. Mechanistically, PACs activate PYRVLO by inhibiting distinct potassium channels in different ways: (1) by scavenging ROS to reduce ROS-sensitive voltage-gated potassium currents and (2) by acting as a channel blocker through direct binding to the cap structure of KCNK3 to inhibit the leak potassium current (Ileak). These results reveal the role of cortical oxidative stress in central hyperalgesia and elucidate the mechanism and potential translational significance of PACs in central analgesia. These findings suggest that the effects of PACs extend beyond their commonly assumed antioxidant or anti-inflammatory effects.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
A force-sensitive adhesion GPCR is required for equilibrioception
Equilibrioception (sensing of balance) is essential for mammals to perceive and navigate the three-dimensional world. A rapid mechanoelectrical transduction (MET) response in vestibular hair cells is crucial for detecting position and motion. Here, we identify the G protein-coupled receptor (GPCR) LPHN2/ADGRL2, expressed on the apical membrane of utricular hair cells, as essential for maintaining normal balance. Loss of LPHN2 specifically in hair cells impaired both balance behavior and the MET response in mice. Functional analyses using hair-cell-specific Lphn2-knockout mice and an LPHN2-specific inhibitor suggest that LPHN2 regulates tip-link-independent MET currents at the apical surface of utricular hair cells. Mechanistic studies in a heterologous system show that LPHN2 converts force stimuli into increased open probability of transmembrane channel-like protein 1 (TMC1). LPHN2-mediated force sensation triggers glutamate release and calcium signaling in utricular hair cells. Importantly, reintroducing LPHN2 into the hair cells of Lphn2-deficient mice restores vestibular function and MET response. Our data reveal that a mechanosensitive GPCR is required for equilibrioception.
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