A biallelic mutation in CACNA2D2 associated with developmental and epileptic encephalopathy affects calcium channel-dependent as well as synaptic functions of αδ-2.

αδ proteins serve as auxiliary subunits of voltage-gated calcium channels and regulate channel membrane expression and current properties. Besides their channel function, αδ proteins regulate synapse formation, differentiation, and synaptic wiring. Considering these important functions, it is not surprising that CACNA2D1-4, the genes encoding for αδ-1 to -4 isoforms, have been implicated in neurological, neurodevelopmental, and neuropsychiatric disorders.

STAT3 in acute myeloid leukemia facilitates natural killer cell-mediated surveillance.

Acute myeloid leukemia (AML) is a heterogenous disease characterized by the clonal expansion of myeloid progenitor cells. Despite recent advancements in the treatment of AML, relapse still remains a significant challenge, necessitating the development of innovative therapies to eliminate minimal residual disease. One promising approach to address these unmet clinical needs is natural killer (NK) cell immunotherapy.

Deletion of the αδ-1 calcium channel subunit increases excitability of mouse chromaffin cells.

High voltage-gated Ca channels (HVCCs) shape the electrical activity and control hormone release in most endocrine cells. HVCCs are multi-subunit protein complexes formed by the pore-forming α and the auxiliary β, αδ and γ subunits. Four genes code for the αδ isoforms.

An ex vivo Model of Paired Cultured Hippocampal Neurons for Bi-directionally Studying Synaptic Transmission and Plasticity.

Synapses provide the main route of signal transduction within neuronal networks. Many factors regulate critical synaptic functions. These include presynaptic calcium channels, triggering neurotransmitter release, and postsynaptic ionotropic receptors, mediating excitatory and inhibitory postsynaptic potentials.

Pathophysiological Roles of Auxiliary Calcium Channel αδ Subunits.

αδ proteins serve as auxiliary subunits of voltage-gated calcium channels, which are essential components of excitable cells such as skeletal and heart muscles, nerve cells of the brain and the peripheral nervous system, as well as endocrine cells. Over the recent years, αδ proteins have been identified as critical regulators of synaptic functions, including the formation and differentiation of synapses. These functions require signalling mechanisms which are partly independent of calcium channels.

αδ-4 and Cachd1 Proteins Are Regulators of Presynaptic Functions.

The αδ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, αδ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism.

Presynaptic αδ subunits are key organizers of glutamatergic synapses.

In nerve cells the genes encoding for αδ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that αδ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular αδ subunit triple-knockout/knockdown model, we demonstrate a failure in presynaptic differentiation evidenced by defective presynaptic calcium channel clustering and calcium influx, smaller presynaptic active zones, and a strongly reduced accumulation of presynaptic vesicle-associated proteins (synapsin and vGLUT).

Phenotypic Characterization and Brain Structure Analysis of Calcium Channel Subunit αδ-2 Mutant (Ducky) and αδ Double Knockout Mice.

Auxiliary αδ subunits of voltage-gated calcium channels modulate channel trafficking, current properties, and synapse formation. Three of the four isoforms (αδ-1, αδ-2, and αδ-3) are abundantly expressed in the brain; however, of the available knockout models, only αδ-2 knockout or mutant mice display an obvious abnormal neurological phenotype. Thus, we hypothesize that the neuronal αδ isoforms may have partially specific as well as redundant functions.

Stabilization of negative activation voltages of Cav1.3 L-Type Ca-channels by alternative splicing.

-->Low voltage-activated Cav1.3 L-type Ca-channels are key regulators of neuronal excitability controlling neuronal development and different types of learning and memory. Their physiological functions are enabled by their negative activation voltage-range, which allows Cav1.

Neuronal αδ proteins and brain disorders.

αδ proteins are membrane-anchored extracellular glycoproteins which are abundantly expressed in the brain and the peripheral nervous system. They serve as regulatory subunits of voltage-gated calcium channels and, particularly in nerve cells, regulate presynaptic and postsynaptic functions independently from their role as channel subunits. αδ proteins are the targets of the widely prescribed anti-epileptic and anti-allodynic drugs gabapentin and pregabalin, particularly for the treatment of neuropathic pain conditions.

Assessment of the Retina of Plp-α-Syn Mice as a Model for Studying Synuclein-Dependent Diseases.

Purpose: Synucleinopathies such as multiple system atrophy (MSA) and Parkinson's disease are associated with a variety of visual symptoms. Functional and morphological retinal aberrations are therefore supposed to be valuable biomarkers for these neurodegenerative diseases. This study examined the retinal morphology and functionality resulting from human α-synuclein (α-Syn) overexpression in the transgenic Plp-α-Syn mouse model.

Auxiliary α2δ1 and α2δ3 Subunits of Calcium Channels Drive Excitatory and Inhibitory Neuronal Network Development.

VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary α2δ subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming α1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of α2δ subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy.

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions.

P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming CaV2.1 α1 subunit and the auxiliary α2δ-2 and β4 subunits.

RBP2 stabilizes slow Cav1.3 Ca channel inactivation properties of cochlear inner hair cells.

Cav1.3 L-type Ca channels (LTCCs) in cochlear inner hair cells (IHCs) are essential for hearing as they convert sound-induced graded receptor potentials into tonic postsynaptic glutamate release. To enable fast and indefatigable presynaptic Ca signaling, IHC Cav1.

Deletion of the Ca Channel Subunit αδ3 Differentially Affects Ca2.1 and Ca2.2 Currents in Cultured Spiral Ganglion Neurons Before and After the Onset of Hearing.

Voltage-gated Ca channels are composed of a pore-forming α subunit and auxiliary β and αδ subunits, which modulate Ca current properties and channel trafficking. So far, the partial redundancy and specificity of α for αδ subunits in the CNS have remained largely elusive. Mature spiral ganglion (SG) neurons express αδ subunit isoforms 1, 2, and 3 and multiple Ca channel subtypes.

Ahnak scaffolds p11/Anxa2 complex and L-type voltage-gated calcium channel and modulates depressive behavior.

Genetic polymorphisms of the L-type voltage-gated calcium channel (VGCC) are associated with psychiatric disorders including major depressive disorder. Alterations of S100A10 (p11) level are also implicated in the etiology of major depressive disorder. However, the existence of an endogenous regulator in the brain regulating p11, L-type VGCC, and depressive behavior has not been known.

Presynaptic αδ-2 Calcium Channel Subunits Regulate Postsynaptic GABA Receptor Abundance and Axonal Wiring.

Presynaptic αδ subunits of voltage-gated calcium channels regulate channel abundance and are involved in glutamatergic synapse formation. However, little is known about the specific functions of the individual αδ isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression of αδ-2 in GABAergic synapses strongly increases clustering of postsynaptic GABARs.

Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2-neo mouse rescued by L-type calcium channel blockers.

Key Points: Tymothy syndrome (TS) is a multisystem disorder featuring cardiac arrhythmias, autism and adrenal gland dysfunction that originates from a de novo point mutation in the gene encoding the Cav1.2 (CACNA1C) L-type channel. To study the role of Cav1.

Calcium Influx and Release Cooperatively Regulate AChR Patterning and Motor Axon Outgrowth during Neuromuscular Junction Formation.

Formation of synapses between motor neurons and muscles is initiated by clustering of acetylcholine receptors (AChRs) in the center of muscle fibers prior to nerve arrival. This AChR patterning is considered to be critically dependent on calcium influx through L-type channels (Ca1.1).

Molecular mimicking of C-terminal phosphorylation tunes the surface dynamics of Ca1.2 calcium channels in hippocampal neurons.

L-type voltage-gated Ca1.2 calcium channels (Ca1.2) are key regulators of neuronal excitability, synaptic plasticity, and excitation-transcription coupling.

Bicistronic CACNA1A Gene Expression in Neurons Derived from Spinocerebellar Ataxia Type 6 Patient-Induced Pluripotent Stem Cells.

Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder that is caused by a CAG trinucleotide repeat expansion in the CACNA1A gene. As one of the few bicistronic genes discovered in the human genome, CACNA1A encodes not only the α1A subunit of the P/Q type voltage-gated Ca channel Ca2.1 but also the α1ACT protein, a 75 kDa transcription factor sharing the sequence of the cytoplasmic C-terminal tail of the α1A subunit.

Administration of secretoneurin is protective in hypoxic-ischemic neonatal brain injury predominantly in the hypoxic-only hemisphere.

Neonatal brain injury is a problem of global importance. To date, no causal therapies are available. A substance with considerable therapeutic potential is the endogenous neuropeptide secretoneurin (SN), which has proven to be beneficial in adult stroke.

Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Ca1.2 Ca Channels at Excitatory Synapses.

Voltage-gated Ca1.2 and Ca1.3 (L-type) Ca channels regulate neuronal excitability, synaptic plasticity, and learning and memory.