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Ischemic Inhibition of Calcium Slow Current in the Heart
Published in Samuel Sideman, Rafael Beyar, Analysis and Simulation of the Cardiac System — Ischemia, 2020
Therefore, it appears that calmodulin also plays a potentiating role in the regulation of the myocardial Ca2+ slow channels. This effect may be mediated by the Ca2+-calmodulin protein kinase and phosphorylation of a protein that affects the functioning of the slow channel (Figure 10). It is possible that a regulatory protein associated with the slow channel, when phosphorylated, acts to make that slow channel become available for voltage activation, i.e., a protein associated with the slow channel may be phosphorylated by the Ca2+-calmodulin-dependent protein kinase, which may, in some manner, potentiate the effects of cAMP-dependent phosphorylation of the slow channel. Thus, it appears that maximal activation of the slow channels requires two separate phosphorylation steps. These may be on the same protein (Figure 10) or on two separate proteins (i.e., two stimulatory regulatory components).
Smooth Muscle
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Smooth muscles do not contain troponin, but they instead have calmodulin, a globular regulatory protein. In smooth muscle, excitation–contraction coupling is achieved by calcium combining with calmodulin; this then activates myosin light chain kinase, a phosphorylating enzyme which phosphorylates the regulatory light chain of myosin.
Timothy Bliss (b. 1940) and Terje Lømo (b. 1935)
Published in Andrew P. Wickens, 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.
A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome
Published in Expert Review of Neurotherapeutics, 2022
An-Sofie Schoonjans, Berten Ceulemans
Rodriguez-Munoz and colleagues demonstrated that fenfluramine inhibits the overactivation of the NMDA receptors through its effect on σ1 receptors [57]. They performed in-vitro assays and tests in an N-methyl-D-aspartate (NMDA)-induced seizure model in CD-1 mice. Fenfluramine, norfenfluramine and an σ1 receptor antagonist all significantly reduced the seizures induced by NMDA. The effect of (nor)fenfluramine was partially reversed by adding a σ1R agonist or by adding a 5-HT2AR antagonist. These data show that (+)fenfluramine and nor(+)fenfluramine reduce NMDA-induced seizures through antagonism of σ1 receptors and agonism of 5-HT2AR. In vitro work showed that fenfluramine act as an antagonist on σ1 receptors and disrupts the association of σ1R and (NR1) subunits of the NMDA receptors. This enables calcium-regulated calmodulin to bind to the subunits, inhibiting further calcium permeation through NMDA-R, and thus preventing its overstimulation. Fenfluramine also enhanced the coupling of inhibitory G-protein coupled receptors with NMDA-R, further restraining its activity.
Myosin light chain kinase regulates intestinal permeability of mucosal homeostasis in Crohn’s disease
Published in Expert Review of Clinical Immunology, 2020
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].