The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by cognitive decline and neuronal degeneration. The formation of amyloid β plaques and neurofibrillary tangles are key morphological features of AD pathology. However, the specific molecules responsible for the cell destruction triggered by amyloid β and tau proteinopathies in AD has not yet been identified.

Calcium release via IPR/RyR channels contributes to the nuclear and mitochondrial Ca signals elicited by neuronal stimulation.

The brain constantly adapts to environmental changes by modifying the expression of genes that enable synaptic plasticity, learning and memory. The expression of several of these genes requires nuclear calcium (Ca) signals, which in turn requires that Ca signals generated by neuronal activity at the synapses or the soma propagate to the nucleus. Since cytoplasmic Ca diffusion is highly restricted, Ca signal propagation to the nucleus requires the participation of other cellular mechanisms.

Pharmacological Targeting of the NMDAR/TRPM4 Death Signaling Complex with a TwinF Interface Inhibitor Prevents Excitotoxicity-Associated Dendritic Blebbing and Organelle Damage.

Focal swellings of dendrites ("dendritic blebbing") together with structural damage of mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks of glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations are generally thought to be caused by the so-called "overactivation" of N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that the activation of extrasynaptic NMDARs, specifically when forming a protein-protein complex with TRPM4, drives these pathological traits.

Ryanodine Receptor Mediated Calcium Release Contributes to Ferroptosis Induced in Primary Hippocampal Neurons by GPX4 Inhibition.

Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. Scant information is available on GPX4-induced ferroptosis in hippocampal neurons.

RyR-mediated Ca release elicited by neuronal activity induces nuclear Ca signals, CREB phosphorylation, and Npas4/RyR2 expression.

The expression of several hippocampal genes implicated in learning and memory processes requires that Ca signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca signals to the nucleus. Here, we present evidence showing that Ca release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons.

Ryanodine receptor-mediated Ca release and atlastin-2 GTPase activity contribute to IP-induced dendritic Ca signals in primary hippocampal neurons.

Neuronal Ca signals are fundamental for synaptic transmission and activity-dependent changes in gene expression. Voltage-gated Ca channels and N-methyl-d-aspartate receptors play major roles in mediating external Ca entry during action potential firing and glutamatergic activity. Additionally, the inositol-1,4,5-trisphosphate receptor (IPR) and the ryanodine receptor (RyR) channels expressed in the endoplasmic reticulum (ER) also contribute to the generation of Ca signals in response to neuronal activity.

Transport along the dendritic endoplasmic reticulum mediates the trafficking of GABAB receptors.

In neurons, secretory organelles within the cell body are complemented by the dendritic endoplasmic reticulum (ER) and Golgi outposts (GOPs), whose role in neurotransmitter receptor trafficking is poorly understood. γ-aminobutyric acid (GABA) type B metabotropic receptors (GABABRs) regulate the efficacy of synaptic transmission throughout the brain. Their plasma membrane availability is controlled by mechanisms involving an ER retention motif and assembly-dependent ER export.

RNA interference of Marlin-1/Jakmip1 results in abnormal morphogenesis and migration of cortical pyramidal neurons.

The formation of the nervous systems requires processes that coordinate proliferation, differentiation and migration of neuronal cells, which extend axons, generate dendritic branching and establish synaptic connections during development. The structural organization and dynamic remodeling of the cytoskeleton and its association to the secretory pathway are critical determinants of cell morphogenesis and migration. Marlin-1 (Jakmip1) is a microtubule-associated protein predominantly expressed in neurons and lymphoid cells.

Location matters: the endoplasmic reticulum and protein trafficking in dendrites.

Neurons are highly polarized, but the trafficking mechanisms that operate in these cells and the topological organization of their secretory organelles are still poorly understood. Particularly incipient is our knowledge of the role of the neuronal endoplasmic reticulum. Here we review the current understanding of the endoplasmic reticulum in neurons, its structure, composition, dendritic distribution and dynamics.

The endoplasmic reticulum and protein trafficking in dendrites and axons.

Neurons are highly polarized cells whose dendrites and axons extend long distances from the cell body to form synapses that mediate neuronal communication. The trafficking of membrane lipids and proteins throughout the neuron is essential for the establishment and maintenance of cell morphology and synaptic function. However, the dynamic shape and spatial organization of secretory organelles, and their role in defining neuronal polarity and the composition of synapses, are not well delineated.

Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABAB receptors.

Slow and persistent synaptic inhibition is mediated by metabotropic GABAB receptors (GABABRs). GABABRs are responsible for the modulation of neurotransmitter release from presynaptic terminals and for hyperpolarization at postsynaptic sites. Postsynaptic GABABRs are predominantly found on dendritic spines, adjacent to excitatory synapses, but the control of their plasma membrane availability is still controversial.

Dendritic assembly of heteromeric gamma-aminobutyric acid type B receptor subunits in hippocampal neurons.

Understanding the mechanisms that control synaptic efficacy through the availability of neurotransmitter receptors depends on uncovering their specific intracellular trafficking routes. gamma-Aminobutyric acid type B (GABA(B)) receptors (GABA(B)Rs) are obligatory heteromers present at dendritic excitatory and inhibitory postsynaptic sites. It is unknown whether synthesis and assembly of GABA(B)Rs occur in the somatic endoplasmic reticulum (ER) followed by vesicular transport to dendrites or whether somatic synthesis is followed by independent transport of the subunits for assembly and ER export throughout the somatodendritic compartment.

Marlin-1 and conventional kinesin link GABAB receptors to the cytoskeleton and regulate receptor transport.

The cytoskeleton and cytoskeletal motors play a fundamental role in neurotransmitter receptor trafficking, but proteins that link GABA(B) receptors (GABA(B)Rs) to the cytoskeleton have not been described. We recently identified Marlin-1, a protein that interacts with GABA(B)R1. Here, we explore the association of GABA(B)Rs and Marlin-1 to the cytoskeleton using a combination of biochemistry, microscopy and live cell imaging.