Calcium binding to calmodulin and its globular domains

Linse, Sara; Helmersson, Anna; Forsén, Sture

doi:10.1016/s0021-9258(18)92938-8

Cited by 462 publications

(301 citation statements)

References 32 publications

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“…Each lobe has two Ca 2+ -binding EF-hands, which can coordinate binding of one Ca 2+ ion for a total of four Ca 2+ ions. Interestingly, the C-lobe of CaM binds Ca 2+ with a six-time higher affinity than the N-lobe, thereby providing CaM with the ability to sense Ca 2+ across a dynamic concentration range [ 155 ]. Moreover, CaM undergoes a conformational change following Ca 2+ binding that can increase or decrease the affinity of CaM to its target protein [ 156 , 157 ], thus allowing CaM to display a wide range of binding and regulatory properties.…”

Section: Na V 16 Regulation By Protein-protein Interactionsmentioning

confidence: 99%

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Zybura

Hudmon

Cummins

2021

Cells

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Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.

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Section: Na V 16 Regulation By Protein-protein Interactionsmentioning

confidence: 99%

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Zybura

Hudmon

Cummins

2021

Cells

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“…The CaM-bound structures suggest the mechanism of Ca 2+ -induced inactivation of TRPV6 and TRPV5 (Hughes et al 2018b;Singh et al 2018b;Dang et al 2019). It has been previously shown that the C-terminal lobe of CaM has higher affinity for Ca 2+ than its N-terminal lobe (Linse et al 1991;James et al 1995). Accordingly, under basal calcium levels, the C-terminal lobe of CaM might always be bound to Ca 2+ and to the distal C-terminus of TRPV6 (Bate et al 2018;Bokhovchuk et al 2018).…”

Section: Inactivation By Calmodulinmentioning

confidence: 97%

Structure and function of the calcium‐selective TRP channel TRPV6

Yelshanskaya

Nadezhdin

Kurnikova

et al. 2020

The Journal of Physiology

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Epithelial calcium channel TRPV6 is a member of the vanilloid subfamily of TRP channels that is permeable to cations and highly selective to Ca 2+ ; it shows constitutive activity regulated negatively by Ca 2+ and positively by phosphoinositol and cholesterol lipids. In this review, we describe the molecular structure of TRPV6 and discuss how its structural elements define its unique functional properties. High Ca 2+ selectivity of TRPV6 originates from the narrow selectivity filter, where Ca 2+ ions are directly coordinated by a ring of anionic aspartate side chains. Divalent cations Ca 2+ and Ba 2+ permeate TRPV6 pore according to the knock-off mechanism, while tight binding of Gd 3+ to the aspartate ring blocks the channel and prevents Na + from permeating the pore. The iris-like channel opening is accompanied by an α-to-π helical transition in the pore-lining transmembrane helix S6. As a result of this transition, the intracellular halves of the S6 helices bend and rotate by about 100 degrees, exposing different residues to the channel pore in the open and closed states. Channel opening is also associated with changes in occupancy of the transmembrane domain lipid binding sites. The inhibitor 2-aminoethoxydiphenyl borate (2-APB) binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helical bundle and shifts open-closed channel equilibrium towards the closed state by outcompeting lipids critical for activation. Ca 2+ inhibits TRPV6 via binding to calmodulin (CaM), which mediates Ca 2+-dependent inactivation. The TRPV6-CaM complex exhibits 1:1 stoichiometry; one TRPV6 tetramer binds both CaM lobes, which adopt a distinct head-to-tail arrangement. The CaM C-terminal lobe plugs the channel through a unique This article is protected by copyright. All rights reserved. 2 cation-π interaction by inserting the side chain of lysine K115 into a tetra-tryptophan cage at the ion channel pore intracellular entrance. Recent studies of TRPV6 structure and function described in this review advance our understanding of the role of this channel in physiology and pathophysiology and inform new therapeutic design.

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“…Each of the two domains contain two EF-hand Ca binding sites. The N-domain of the protein has a lower Ca binding affinity than the C-domain [54,55]. Upon Ca binding, the hydrophobic pockets in both domains become exposed, thereby allowing CaM to bind its several intracellular targets, including RyR2, LTCC and Na channel (Nav 1.5) [56].…”

Section: Cpvt Linked To Calmodulin Mutationsmentioning

confidence: 99%

Molecular Mechanism and Current Therapies for Catecholaminergic Polymorphic Ventricular Tachycardia

Liu¹,

Tow²,

Bonilla³

2022

Cardiac Arrhythmias - Translational Approach From Pathophysiology to Advanced Care

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The rhythmic contraction of the heart relies on tightly regulated calcium (Ca) release from the sarcoplasmic reticulum (SR) Ca release channel, Ryanodine receptor (RyR2). Genetic mutations in components of the calcium release unit such as RyR2, cardiac calsequestrin and other proteins have been shown to cause a genetic arrhythmic syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT). This book chapter will focus on the following: (1) to describing CPVT as a stress-induced cardiac arrhythmia syndrome and its genetic causes. (2) Discussing the regulation of SR Ca release, and how dysregulation of Ca release contributes to arrhythmogenesis. (3) Discussing molecular mechanisms of CPVT with a focus on impaired Ca signaling refractoriness as a unifying mechanism underlying different genetic forms of CPVT. (4) Discussing pharmacological approaches as CPVT treatments as well as other potential future therapies. Since dysregulated SR Ca release has been implicated in multiple cardiac disorders including heart failure and metabolic heart diseases, knowledge obtained from CPVT studies will also shed light on the development of therapeutic approaches for these devastating cardiac dysfunctions as a whole.

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Calcium binding to calmodulin and its globular domains

Cited by 462 publications

References 32 publications

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Structure and function of the calcium‐selective TRP channel TRPV6

Molecular Mechanism and Current Therapies for Catecholaminergic Polymorphic Ventricular Tachycardia

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