Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85721, USA; Neuroscience Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85721, USA; Comprehensive Pain and Addiction Center, University of Arizona Health Sciences, 85721, USA; The Center of Excellence in Addiction Studies, University of Arizona, Tucson, AZ 85721, USA; Department of Neuroscience, College of Science, University of Arizona, Tucson, AZ 85721, USA; James C. Wyant College of Optical Sciences, The University of Arizona, Tucson, AZ 85721, USA. Electronic address:
Published: October 2022
AI Article Synopsis
Article Abstract
Chronic pain remains a disabling disease with limited therapeutic options. Pyramidal neurons in the prefrontal cortex (PFC) express excitatory G-coupled 5-HT receptors (5-HTR) and their effector system, the inhibitory Kv7 ion channel. While recent publications show these cells innervate brainstem regions important for regulating pain, the cellular mechanisms underlying the transition to chronic pain are not well understood. The present study examined whether local blockade of 5-HTR or enhanced Kv7 ion channel activity in the PFC would attenuate mechanical allodynia associated with spared nerve injury (SNI) in rats. Following SNI, we show that inhibition of PFC 5-HTRs with M100907 or opening of PFC Kv7 channels with retigabine reduced mechanical allodynia. Parallel proteomic and RNAScope experiments evaluated 5-HTR/Kv7 channel protein and mRNA. Our results support the role of 5-HTRs and Kv7 channels in the PFC in the maintenance of chronic pain.
Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes such as have also been implicated in AF pathogenesis partly by the development of an atrial myopathy, but the underlying mechanisms are poorly understood. While truncating variants (tvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear.
Seizure is among the most severe FDA black box warnings of neurotoxicity reported on drug labels. Gaining a better mechanistic understanding of off-targets causative of seizure will improve identification of potential seizure risks preclinically. In the present study, we evaluated an in vitro panel of 9 investigational (Cav2.
Zotepine is a second-generation antipsychotic that demonstrates significant efficacy in antagonizing D and 5-HT receptors. Although clinical investigations have shown that administering zotepine is associated with an increased prevalence of hyperglycemia and a heightened risk of cardiovascular disease, the side effects of zotepine on voltage-gated K (Kv) channels have not been established. Zotepine suppressed the vascular Kv channels in rabbit coronary arterial smooth muscle cells in a concentration-dependent manner, with an IC of 5.
Background And Purpose: Paracetamol has been found to alleviate inflammatory pain by modulating K7 channels. Its metabolite N-acetyl-4-benzoquinoneimine (NAPQI) increases currents through these channels via a stretch of three cysteine residues in the channel S2-S3 linker. Through this effect, the excitability of neurons in the pain pathway is dampened.
* The review discusses the physiological roles of K7.4 and K7.5 channels and recent progress in developing selective modulators that could lead to innovative treatments for hypertension.
* Although research has mainly targeted K7.2 and K7.3 channels, there’s a growing need to explore K7.4 and K7.5 for specific, safe, and effective new compounds to enhance blood pressure control in the future.
