Loss of the auxiliary αδ voltage-sensitive calcium channel subunit impairs bone formation and anabolic responses to mechanical loading.

Voltage-sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α) subunit of VSCCs allows Ca influx, auxiliary subunits regulate the biophysical properties of the pore. The αδ subunit influences gating kinetics of the α pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of αδ in vivo remains unknown.

The Interplay Between Splicing of Two Exon Combinations Differentially Affects Membrane Targeting and Function of Human Ca2.2.

N-type calcium channels (Ca2.2) are predominantly localized in presynaptic terminals, and are particularly important for pain transmission in the spinal cord. Furthermore, they have multiple isoforms, conferred by alternatively spliced or cassette exons, which are differentially expressed.

Virtual Reality for IMMunisation (VRIMM) pain in young children: Results of a randomised controlled trial in general practice.

Background And Objectives: Virtual reality (VR) may be useful for reducing needle-based pain and distress. Our objective was to compare VR against standard care for children undergoing routine four-year-old immunisations.

Method: This was a randomised controlled superiority trial conducted in a single suburban general practice, comparing a VR sequence of an interactive marine adventure to standard care (parental comfort, distraction of child).

Ancient Clostridium DNA and variants of tetanus neurotoxins associated with human archaeological remains.

The analysis of microbial genomes from human archaeological samples offers a historic snapshot of ancient pathogens and provides insights into the origins of modern infectious diseases. Here, we analyze metagenomic datasets from 38 human archaeological samples and identify bacterial genomic sequences related to modern-day Clostridium tetani, which produces the tetanus neurotoxin (TeNT) and causes the disease tetanus. These genomic assemblies had varying levels of completeness, and a subset of them displayed hallmarks of ancient DNA damage.

T-type Ca and persistent Na currents synergistically elevate ventral, not dorsal, entorhinal cortical stellate cell excitability.

Dorsal and ventral medial entorhinal cortex (mEC) regions have distinct neural network firing patterns to differentially support functions such as spatial memory. Accordingly, mEC layer II dorsal stellate neurons are less excitable than ventral neurons. This is partly because the densities of inhibitory conductances are higher in dorsal than ventral neurons.

Distinct pools of synaptic vesicles are released by different calcium channels.

Mueller et al. [1] uncover distinct roles for Ca1 and Ca2 channels in neurotransmitter release at the C. elegans neuromuscular junction.

The importance of cache domains in αδ proteins and the basis for their gabapentinoid selectivity.

In this hybrid review, we have first collected and reviewed available information on the structure and function of the enigmatic cache domains in αδ proteins. These are organized into two double cache (dCache_1) domains, and they are present in all αδ proteins. We have also included new data on the key function of these domains with respect to amino acid and gabapentinoid binding to the universal amino acid-binding pocket, which is present in αδ-1 and αδ-2.

Capsaicin-Induced Endocytosis of Endogenous Presynaptic Ca2.2 in DRG-Spinal Cord Co-Cultures Inhibits Presynaptic Function.

The N-type calcium channel, Ca2.2 is key to neurotransmission from the primary afferent terminals of dorsal root ganglion (DRG) neurons to their postsynaptic targets in the spinal cord. In this study, we have utilized Ca2.

Nerve injury increases native Ca V 2.2 trafficking in dorsal root ganglion mechanoreceptors.

Neuronal N-type (Ca V 2.2) voltage-gated calcium channels are essential for neurotransmission from primary afferent terminals in the dorsal horn. In this study, we have used a knockin mouse containing Ca V 2.

Involvement of Ca 2.2 channels and α δ-1 in homeostatic synaptic plasticity in cultured hippocampal neurons.

In the mammalian brain, presynaptic Ca 2 channels play a pivotal role in synaptic transmission by mediating fast neurotransmitter exocytosis via influx of Ca into the active zone of presynaptic terminals. However, the distribution and modulation of Ca 2.2 channels at plastic hippocampal synapses remains to be elucidated.

ADAM17 Mediates Proteolytic Maturation of Voltage-Gated Calcium Channel Auxiliary αδ Subunits, and Enables Calcium Current Enhancement.

The auxiliary αδ subunits of voltage-gated calcium (Ca) channels are key to augmenting expression and function of Ca1 and Ca2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The αδ proteins are translated as preproteins encoding both α and δ, and post-translationally proteolyzed into α and δ subunits, which remain associated as a complex. In this study, we have identified ADAM17 as a key protease involved in proteolytic processing of pro-αδ-1 and αδ-3 subunits.

Proteolytic regulation of calcium channels - avoiding controversy.

The publication of papers containing data obtained with suboptimal rigor in the experimental design and choice of key reagents, such as antibodies, can result in a lack of reproducibility and generate controversy that can both needlessly divert resources and, in some cases, damage public perception of the scientific enterprise. This exemplary paper by Buonarati (2018) shows how a previously published, potentially important paper on calcium channel regulation falls short of the necessary mark, and aims to resolve the resulting controversy.

Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.

Voltage-gated calcium (CaV) channels form three subfamilies (CaV1-3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1-4.

Amino acid sensor conserved from bacteria to humans.

SignificanceAmino acids are the building blocks of life and important signaling molecules. Despite their common structure, no universal mechanism for amino acid recognition by cellular receptors is currently known. We discovered a simple motif, which binds amino acids in various receptor proteins from all major life-forms.

Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit αδ-1 but not αδ-3.

N-type voltage-gated calcium channels (Ca2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary αδ and β subunits. All four mammalian αδ subunits enhance calcium currents through Ca1 and Ca2 channels, and this increase is attributed, in part, to increased Ca expression at the plasma membrane.

How Postdoctoral Research in Paul Greengard's Laboratory Shaped My Scientific Career, Although I Never Did Another Phosphorylation Assay.

In this short review, I describe from personal experience how every step in the career of any scientist, no matter how disjointed and pragmatic each might seem at the time, will almost inevitably meld together, to help us all tackle novel projects. My postdoctoral research in Paul Greengard's laboratory, where I investigated neurotransmitter-mediated phosphorylation of Synapsin I, was instrumental in my career progression, and Paul's support was instrumental in my ability to make a leap into independent research.

Functions of Presynaptic Voltage-gated Calcium Channels.

Voltage-gated calcium channels are the principal conduits for depolarization-mediated Ca entry into excitable cells. In this review, the biophysical properties of the relevant members of this family of channels, those that are present in presynaptic terminals, will be discussed in relation to their function in mediating neurotransmitter release. Voltage-gated calcium channels have properties that ensure they are specialized for particular roles, for example, differences in their activation voltage threshold, their various kinetic properties, and their voltage-dependence of inactivation.

The VRIMM study: Virtual Reality for IMMunisation pain in young children-protocol for a randomised controlled trial.

Introduction: Pain caused by routine immunisations is distressing to children, their parents and those administering injections. If poorly managed, it can lead to anxiety about future medical procedures, needle phobia and avoidance of future vaccinations and other medical treatment. Several strategies, such as distraction, are used to manage the distress associated with routine immunisations.

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release.

Chemical synapses are heterogeneous junctions formed between neurons that are specialized for the conversion of electrical impulses into the exocytotic release of neurotransmitters. Voltage-gated Ca channels play a pivotal role in this process as they are the major conduits for the Ca ions that trigger the fusion of neurotransmitter-containing vesicles with the presynaptic membrane. Alterations in the intrinsic function of these channels and their positioning within the active zone can profoundly alter the timing and strength of synaptic output.

Fight or flight: The culprit is lurking in the neighbourhood.

The fight-or-flight response is studied by all students of Physiology as a concerted bodily response to danger. Liu et al (2020) have now revealed its mechanism, after surveying the proteomic neighbourhood around the cardiac calcium channels in a study which is a tour-de-force of modern biological techniques.

FMRP regulates presynaptic localization of neuronal voltage gated calcium channels.

Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism, results from the loss of fragile X mental retardation protein (FMRP). We have recently identified a direct interaction of FMRP with voltage-gated Ca channels that modulates neurotransmitter release. In the present study we used a combination of optophysiological tools to investigate the impact of FMRP on the targeting of voltage-gated Ca channels to the active zones in neuronal presynaptic terminals.

Introduction to the Theme "Ion Channels and Neuropharmacology: From the Past to the Future".

"Ion Channels and Neuropharmacology: From the Past to the Future" is the main theme of articles in Volume 60 of the . Reviews in this volume discuss a wide spectrum of therapeutically relevant ion channels and GPCRs with a particular emphasis on structural studies that elucidate drug binding sites and mechanisms of action. The regulation of ion channels by second messengers, including Ca and cyclic AMP, and lipid mediators is also highly relevant to several of the ion channels discussed, including KCNQ channels, HCN channels, L-type Ca channels, and AMPA receptors, as well as the aquaporin channels.

IgGs from patients with amyotrophic lateral sclerosis and diabetes target Caαδ1 subunits impairing islet cell function and survival.

Patients with amyotrophic lateral sclerosis (ALS) often show hallmarks of type 2 diabetes mellitus (T2DM). However, the causal link between ALS and T2DM has remained a mystery. We now demonstrate that 60% of ALS patients with T2DM (ALS-T2DM) have sera that exaggerated K-induced increases in cytosolic free Ca concentration ([Ca]) in mouse islet cells.

Disruption of the Key Ca Binding Site in the Selectivity Filter of Neuronal Voltage-Gated Calcium Channels Inhibits Channel Trafficking.

Voltage-gated calcium channels are exquisitely Ca selective, conferred primarily by four conserved pore-loop glutamate residues contributing to the selectivity filter. There has been little previous work directly measuring whether the trafficking of calcium channels requires their ability to bind Ca in the selectivity filter or to conduct Ca. Here, we examine trafficking of neuronal Ca2.

Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal.

We reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes.