Nav1.7 is essential for nociceptor action potentials in the mouse in a manner independent of endogenous opioids.

Loss-of-function mutations in Nav1.7, a voltage-gated sodium channel, cause congenital insensitivity to pain (CIP) in humans, demonstrating that Nav1.7 is essential for the perception of pain.

Cryo-EM reveals an unprecedented binding site for Na1.7 inhibitors enabling rational design of potent hybrid inhibitors.

The voltage-gated sodium (Na) channel Na1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available Na channel-blocking drugs are not selective among the nine Na channel subtypes, Na1.

Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (Na) 1.7 with Potent Analgesic Activity.

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide Na1.7 inhibitors that are selective for Na1.7 over Na1.

Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors.

Strong human genetic evidence points to an essential contribution of the voltage-gated sodium channel Nav1.7 to pain sensation: loss of Nav1.7 function leads to congenital insensitivity to pain, whereas gain-of-function mutations in the gene that encodes Nav1.

A novel NMDA receptor positive allosteric modulator that acts via the transmembrane domain.

Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD.

Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist.

Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies.

Altered GluN2B NMDA receptor function and synaptic plasticity during early pathology in the PS2APP mouse model of Alzheimer's disease.

GluN2B subunit containing NMDARs (GluN2B-NMDARs) mediate pathophysiological effects of acutely applied amyloid beta (Aβ), including impaired long-term potentiation (LTP). However, in transgenic Alzheimer's disease (AD) mouse models which feature gradual Aβ accumulation, the function of GluN2B-NMDARs and their contribution to synaptic plasticity are unknown. Therefore, we examined the role of GluN2B-NMDARs in synaptic function and plasticity in the hippocampus of PS2APP transgenic mice.

Histone deacetylase 2 cell autonomously suppresses excitatory and enhances inhibitory synaptic function in CA1 pyramidal neurons.

Histone deacetylase 2 (HDAC2) negatively regulates excitatory synapse number and memory performance. However, whether HDAC2 regulation of excitatory synapses occurs in a cell-autonomous manner and whether HDAC2 regulates inhibitory synaptic functions are not well understood. To examine these aspects of HDAC2 function, we used sparse transfection of rat hippocampal slice cultures and whole-cell recordings in pyramidal neurons.

GluN2B antagonism affects interneurons and leads to immediate and persistent changes in synaptic plasticity, oscillations, and behavior.

Although antagonists to GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) have been widely considered to be neuroprotective under certain pathological conditions, their immediate and lasting impacts on synaptic, circuit, and cognitive functions are poorly understood. In hippocampal slices, we found that the GluN2B-selective antagonist Ro25-6981 (Ro25) reduced synaptic NMDAR responses and consequently neuronal output in a subpopulation of GABAergic interneurons, but not pyramidal neurons. Consistent with these effects, Ro25 reduced GABAergic responses in pyramidal neurons and hence could affect circuit functions by altering the excitation/inhibition balance in the brain.

RIM genes differentially contribute to organizing presynaptic release sites.

Tight coupling of Ca(2+) channels to the presynaptic active zone is critical for fast synchronous neurotransmitter release. RIMs are multidomain proteins that tether Ca(2+) channels to active zones, dock and prime synaptic vesicles for release, and mediate presynaptic plasticity. Here, we use conditional knockout mice targeting all RIM isoforms expressed by the Rims1 and Rims2 genes to examine the contributions and mechanism of action of different RIMs in neurotransmitter release.

RIM proteins activate vesicle priming by reversing autoinhibitory homodimerization of Munc13.

At a synapse, the presynaptic active zone mediates synaptic vesicle exocytosis. RIM proteins are active zone scaffolding molecules that--among others--mediate vesicle priming and directly or indirectly interact with most other essential presynaptic proteins. In particular, the Zn²+ finger domain of RIMs binds to the C₂A domain of the priming factor Munc13, which forms a homodimer in the absence of RIM but a heterodimer with it.

RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interaction.

At a synapse, fast synchronous neurotransmitter release requires localization of Ca(2+) channels to presynaptic active zones. How Ca(2+) channels are recruited to active zones, however, remains unknown. Using unbiased yeast two-hybrid screens, we here identify a direct interaction of the central PDZ domain of the active-zone protein RIM with the C termini of presynaptic N- and P/Q-type Ca(2+) channels but not L-type Ca(2+) channels.

ELKS2alpha/CAST deletion selectively increases neurotransmitter release at inhibitory synapses.

The presynaptic active zone is composed of a protein network that contains ELKS2alpha (a.k.a.

RIM1alpha and RIM1beta are synthesized from distinct promoters of the RIM1 gene to mediate differential but overlapping synaptic functions.

At a synapse, presynaptic terminals form a specialized area of the plasma membrane called the active zone that mediates neurotransmitter release. RIM1alpha is a multidomain protein that constitutes a central component of the active zone by binding to other active zone proteins such as Munc13 s, alpha-liprins, and ELKS, and to synaptic vesicle proteins such as Rab3 and synaptotagmin-1. In mice, knockout of RIM1alpha significantly impairs synaptic vesicle priming and presynaptic long-term plasticity, but is not lethal.

Sequential postsynaptic maturation governs the temporal order of GABAergic and glutamatergic synaptogenesis in rat embryonic cultures.

Sequential formation of GABAergic and glutamatergic synapses is thought to be crucial for constructing the stereotypic neural networks during brain development. However, why GABAergic synapses are formed earlier than glutamatergic synapses in the developing brain is not well understood. We used electrophysiology and fluorescence imaging to study GABAergic and glutamatergic synaptogenesis in embryonic hypothalamic cultures, which contain approximately 40% GABAergic and approximately 60% glutamatergic neurons.

GODZ-mediated palmitoylation of GABA(A) receptors is required for normal assembly and function of GABAergic inhibitory synapses.

Golgi-specific DHHC (Asp-His-His-Cys) zinc finger protein (GODZ) is a DHHC family palmitoyl acyltransferase that is implicated in palmitoylation and regulated trafficking of diverse substrates that function either at inhibitory or excitatory synapses. Of particular interest is the gamma2 subunit of GABA(A) receptors, which is required for targeting these receptors to inhibitory synapses. Here, we report that GODZ and, to a lesser extent, its close paralog sertoli cell gene with a zinc finger domain-beta (SERZ-beta) are the main members of the DHHC family of enzymes that are able to palmitoylate the gamma2 subunit in heterologous cells.

Hyperpolarization-activated, cyclic nucleotide-gated cation channels: roles in the differential electrophysiological properties of rat primary afferent neurons.

The large, medium-sized, and small neurons of the dorsal root ganglion (DRG) have different functions in the processing of various senses. Hyperpolarization-activated, cyclic nucleotide-gated channels (HCN) contribute greatly to neuronal excitability. In the present study, which used whole-cell patch clamp techniques and immunohistochemical staining methods, the electrophysiological properties of DRG neurons were systematically compared, and the roles of HCN-1, -2, and -4 were examined.

Cyclothiazide potently inhibits gamma-aminobutyric acid type A receptors in addition to enhancing glutamate responses.

Ionotropic glutamate and gamma-aminobutyric acid type A (GABAA) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABAA receptors.

Formation of an endophilin-Ca2+ channel complex is critical for clathrin-mediated synaptic vesicle endocytosis.

A tight balance between synaptic vesicle exocytosis and endocytosis is fundamental to maintaining synaptic structure and function. Calcium influx through voltage-gated Ca2+ channels is crucial in regulating synaptic vesicle exocytosis. However, much less is known about how Ca2+ regulates vesicle endocytosis or how the endocytic machinery becomes enriched at the nerve terminal.