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Medicine Jul 2023Studies in the 1920s found that botulinum neurotoxin type A (BoNT/A) inhibited the activity of motor and parasympathetic nerve endings, confirmed several decades later...
Studies in the 1920s found that botulinum neurotoxin type A (BoNT/A) inhibited the activity of motor and parasympathetic nerve endings, confirmed several decades later to be due to decreased acetylcholine release. The 1970s were marked by studies of cellular mechanisms aided by use of neutralizing antibodies as pharmacologic tools: BoNT/A disappeared from accessibility to neutralizing antibodies within minutes, although it took several hours for onset of muscle weakness. The multi-step mechanism was experimentally confirmed and is now recognized to consist broadly of binding to nerve terminals, internalization, and lysis or cleavage of a protein (SNAP-25: synaptosomal associated protein-25 kDa) that is part of the SNARE (Soluble NSF Attachment protein REceptor) complex needed for synaptic vesicle docking and fusion. Clinical use of the BoNT/A product onabotulinumtoxinA was based on its ability to reduce muscle contractions via inhibition of acetylcholine from motor terminals. Sensory mechanisms of onabotulinumtoxinA have now been identified, supporting its successful treatment of chronic migraine and urgency in overactive bladder. Exploration into migraine mechanisms led to anatomical studies documenting pain fibers that send axons through sutures of the skull to outside the head-a potential route by which extracranial injections could affect intracranial processes. Several clinical studies have also identified benefits of onabotulinumtoxinA in major depression, which have been attributed to central responses induced by feedback from facial muscle and skin movement. Overall, the history of BoNT/A is distinguished by basic science studies that stimulated clinical use and, conversely, clinical observations that spurred basic research into novel mechanisms of action.
Topics: Humans; Botulinum Toxins, Type A; Acetylcholine; Urinary Bladder, Overactive; Migraine Disorders; Muscle Contraction
PubMed: 37499078
DOI: 10.1097/MD.0000000000032372 -
ELife Jun 2023Ring-like structures made up of caveolae appear to drive the development of membrane invaginations called T-tubules which are important for muscle contraction.
Ring-like structures made up of caveolae appear to drive the development of membrane invaginations called T-tubules which are important for muscle contraction.
Topics: Caveolin 1; Caveolae; Endocytosis
PubMed: 37339063
DOI: 10.7554/eLife.88954 -
Annual Review of Biochemistry Jun 2023Muscles are essential for movement and heart function. Contraction and relaxation of muscles rely on the sliding of two types of filaments-the thin filament and the... (Review)
Review
Muscles are essential for movement and heart function. Contraction and relaxation of muscles rely on the sliding of two types of filaments-the thin filament and the thick myosin filament. The thin filament is composed mainly of filamentous actin (F-actin), tropomyosin, and troponin. Additionally, several other proteins are involved in the contraction mechanism, and their malfunction can lead to diverse muscle diseases, such as cardiomyopathies. We review recent high-resolution structural data that explain the mechanism of action of muscle proteins at an unprecedented level of molecular detail. We focus on the molecular structures of the components of the thin and thick filaments and highlight the mechanisms underlying force generation through actin-myosin interactions, as well as Ca-dependent regulation via the dihydropyridine receptor, the ryanodine receptor, and troponin. We particularly emphasize the impact of cryo-electron microscopy and cryo-electron tomography in leading muscle research into a new era.
Topics: Actins; Cryoelectron Microscopy; Muscle Contraction; Troponin; Myosins; Calcium
PubMed: 37001141
DOI: 10.1146/annurev-biochem-052521-042909