Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective Na1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain.

Introduction: There is a high unmet need for safe and effective non-opioid medicines to treat moderate to severe pain without risk of addiction. Voltage-gated sodium channel 1.8 (Na1.

Dual mechanisms contribute to enhanced voltage dependence of an electric fish potassium channel.

The voltage dependence of different voltage-gated potassium channels, described by the voltage at which half of the channels are open (V), varies over a range of 80 mV and is influenced by factors such as the number of positive gating charges and the identity of the hydrophobic amino acids in the channel's voltage sensor (S4). Here we explore by experimental manipulations and molecular dynamics simulation the contributions of two derived features of an electric fish potassium channel (Kv1.7a) that is among the most voltage-sensitive Shaker family potassium channels known.

Electrostatic Tuning of a Potassium Channel in Electric Fish.

Molecular variation contributes to the evolution of adaptive phenotypes, though it is often difficult to understand precisely how. The adaptively significant electric organ discharge behavior of weakly electric fish is the direct result of biophysical membrane properties set by ion channels. Here, we describe a voltage-gated potassium-channel gene in African electric fishes that is under positive selection and highly expressed in the electric organ.

Differential Dopamine Regulation of Ca(2+) Signaling and Its Timing Dependence in the Nucleus Accumbens.

Dopamine action in the nucleus accumbens (NAc) is thought to drive appetitive behavior and Pavlovian reward learning. However, it remains controversial how dopamine achieves these behavioral effects by regulating medium spiny projection neurons (MSNs) of the NAc, especially on a behaviorally relevant timescale. Metabotropic glutamate receptor (mGluR)-induced Ca(2+) signaling dependent on the Ca(2+)- releasing messenger inositol 1,4,5-triphosphate (IP3) plays a critical role in controlling neuronal excitability and synaptic plasticity.

"Brain sex differentiation" in teleosts: Emerging concepts with potential biomarkers.

"Brain sex differentiation" in teleosts is a contentious topic of research as most of the earlier reports tend to suggest that gonadal sex differentiation drives brain sex differentiation. However, identification of sex-specific marker genes in the developing brain of teleosts signifies brain-gonadal interaction during early sexual development in lower vertebrates. In this context, the influence of gonadotropin-releasing hormone (GnRH)-gonadotropin (GTH) axis on gonadal sex differentiation, if any requires in depth analysis.

Spatiotemporal integration of developmental cues in neural development.

Nervous system development relies on the generation of neurons, their differentiation and establishment of synaptic connections. These events exhibit remarkable plasticity and are regulated by many developmental cues. Here, we review the mechanisms of three classes of these cues: morphogenetic proteins, electrical activity, and the environment.

Inositol 1,4,5-triphosphate drives glutamatergic and cholinergic inhibition selectively in spiny projection neurons in the striatum.

The striatum is critically involved in the selection of appropriate actions in a constantly changing environment. The spiking activity of striatal spiny projection neurons (SPNs), driven by extrinsic glutamatergic inputs, is shaped by local GABAergic and cholinergic networks. For example, it is well established that different types of GABAergic interneurons, activated by extrinsic glutamatergic and local cholinergic inputs, mediate powerful feedforward inhibition of SPN activity.

Dynamic regulation of neurotransmitter specification: relevance to nervous system homeostasis.

During nervous system development the neurotransmitter identity changes and coexpression of several neurotransmitters is a rather generalized feature of developing neurons. In the mature nervous system, different physiological and pathological circumstances recreate this phenomenon. The rules of neurotransmitter respecification are multiple.

Interplay between electrical activity and bone morphogenetic protein signaling regulates spinal neuron differentiation.

A gradient of bone morphogenetic proteins (BMPs) along the dorsoventral axis of the spinal cord is necessary for the specification of dorsal neurons. Concurrently, a gradient of calcium-mediated electrical activity is present in the developing spinal cord but in an opposing ventrodorsal direction. Whether BMPs and electrical activity interact in embryonic spinal neurons remains unknown.

Electrical activity as a developmental regulator in the formation of spinal cord circuits.

Spinal cord development is a complex process involving generation of the appropriate number of cells, acquisition of distinctive phenotypes and establishment of functional connections that enable execution of critical functions such as sensation and locomotion. Here we review the basic cellular events occurring during spinal cord development, highlighting studies that demonstrate the roles of electrical activity in this process. We conclude that the participation of different forms of electrical activity is evident from the beginning of spinal cord development and intermingles with other developmental cues and programs to implement dynamic and integrated control of spinal cord function.