Timothy Bliss (b. 1940) and Terje Lømo (b. 1935)
Andrew P. Wickens in Key Thinkers in Neuroscience, 2018
The flow of calcium into the dentate cell is crucial for generating LTP probably because it acts as an intracellular messenger that activates a number of proteins involved in changing cellular function. One such protein is calmodulin, which has a conformation similar to a flower with four petals. When calcium binds to calmodulin, it changes its shape, enabling binding to a group of proteins called protein kinases. One important kinase is the enzyme calcium/calmodulin-dependent kinase II (CaMK II). The activity of this chemical continues long after the calcium levels have returned to normal and mimics to some extent the time course of LTP. Moreover, drugs that inhibit CaMK II are also effective in blocking LTP. The exact mechanism by which CaMK II regulates LTP remains unclear – although one possibility is that it increases the number of glutamate receptors at the synapse in a process called “up-regulation”, thereby making the cell more excitable. Indeed, in support of this, calcium increases protein kinase activity that is known to affect chemicals involved in gene transcription.
Anatomy and Physiology of the Autonomic Nervous System
Kenneth J. Broadley in Autonomic Pharmacology, 2017
Smooth muscle contraction is thought to occur in a similar fashion to that in skeletal muscle, although at a slower rate, probably because of a reduced availability of ATP as an energy source. According to the sliding-filament theory, actin and myosin filaments form cross-bridges as a result of which the two myofilaments slide past each other. Unlike skeletal muscle, however, there appears to be no troponin, the calcium-binding protein on the actin myofilament that regulates actin-myosin cross-bridging. Calmodulin is the calcium-binding protein of smooth muscle. Smooth muscle cells have an abundant sarcoplasmic reticulum (SR). The rough or granular endoplasmic reticulum (ER) is the site of synthesis of new membranes, filaments and glycogen. The smooth ER (SR) is probably a site of storage of Ca2+ and release. Although control of contractile mechanisms is dependent upon intracellular Ca2+, it appears that only a minor contribution comes from this intracellular storage site. The transverse or T tubules, which form a continuation of the sarcolemma and pass into skeletal muscle fibres to connect with the SR, are absent in smooth muscle. The roles of myosin light-chain kinase, calmodulin and Ca2+ in the contractile responses of smooth muscle are described in Chapter 13.
Receptor-Ligand Interactions that are Disaproportionate With Their Physiological Effects
John C. Matthews in Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
Calmodulin is a cytoplasmic protein that functions to bind calcium. The calcium-calmodulin complex, in turn, binds to various enzymes and proteins in the cell to alter their activities, thereby producing the physiological effect. Each calmodulin molecule has four binding sites for calcium, which, like hemoglobin, exhibit cooperativity. In the calcium-calmodulin system the calcium enters the cell cytoplasm from outside the cell through calcium channels or it is released from stores in the endoplasmic reticulum. The calmodulin, in its role in signal transduction, needs to be able to respond in a nearly all-or-none fashion to calcium concentration changes. It must go from a near zero binding site occupancy to near fully occupied binding sites over a very narrow concentration range when calcium enters the cytoplasm. The calmodulin must then go from near fully occupied to near fully unoccupied over the same very narrow concentration range as the calcium is pumped out of the cytoplasm. The cooperativity of its interaction with calcium permits calmodulin to function in the manner required.
Myosin light chain kinase regulates intestinal permeability of mucosal homeostasis in Crohn’s disease
Published in Expert Review of Clinical Immunology, 2020
Yiran Yao, Qi Feng, Jun Shen
Many studies have demonstrated how MLCK directly regulates the ability of the cytoskeleton to activate the TJ barrier [48,53,54]. Ca2+/calmodulin-dependent MLCK phosphorylates the myosin RLC and activates myosin in the smooth muscle. Then, ATPase in the myosin head is activated to hydrolyze ATP, thereby converting the chemical energy to mechanical forces and motion [55]. At the same time, actin assembles to form actin filaments. Then, the heavy chain motor domain of myosin reversibly binds to actin filaments, leading to cyclic interaction between actin and myosin. With hydrolyzation of ATP (the basis of energy) and assembly of actin (the basis of structure), interaction between MLCK and skeletal proteins contributes to the interplay and contraction of skeletal proteins, finally leading to contraction of the intestinal cells [39]. With contraction of the cytoskeleton, the paracellular pathways sealed by the TJ are activated to increase intestinal permeability. Additionally, Rho-associated kinase (ROCK) has a similar role in myosin phosphorylation and activation [56].
The role of synaptic biomarkers in the spectrum of neurodegenerative diseases
Published in Expert Review of Proteomics, 2020
Sonia Mazzucchi, Giovanni Palermo, Nicole Campese, Alessandro Galgani, Alessandra Della Vecchia, Andrea Vergallo, Gabriele Siciliano, Roberto Ceravolo, Harald Hampel, Filippo Baldacci
Ng is a 78 aa neuron-specific post-synaptic somato-dendritic protein. It is one of the most abundant calmodulin-binding proteins and is mainly expressed by excitatory neurons of the cerebral cortex and hippocampus. High levels can be measured in amygdala, caudate, and putamen, whereas it is poorly expressed or absent in other brain regions as the thalamus, cerebellum, brainstem, and the spinal cord [5]. The protein can be found in neurons but is not expressed by glial cells. Ng regulates synaptic activity, mainly LTP, through its binding to calmodulin that is increased in the presence of low calcium concentrations and inhibited by large calcium amounts. In animal models, Ng overexpression demonstrated to enhance LTP and improve cognitive performances, whereas in Ng knockout mice memory deficits were reported, probably due to an impairment or even a block of LTP [8]. Furthermore, preclinical studies highlighted an age-dependent reduction of Ng mRNA in several brain regions, including the hippocampus [28].
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
In the past, multi-generational families or large groups of affected patients were needed for genetic analyses in order to identify causative variants. But, with advances in high throughput genetic sequencing, even very small groups of affected patients have been used to identify very rare mutations. Recently, exome sequencing in just two infants suffering from frequent cardiac arrests was used to identify de novo mutations in the calmodulin genes (CALM1, CALM2) as the causes of highly malignant LQTS [116]. Another calmodulin gene, CALM 3, has also been implicated. Rare variants of these genes that develop de novo cause very severe LQTS with atypical features (sinus bradycardia and atrioventricular conduction delay), occurring in infancy or early childhood. In patients with such presentations, genetic testing for CALM 1–3 should be considered [37]. As genetic analysis techniques advance, more and more rare causative variants will no doubt be identified.
Related Knowledge Centers
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