Screening G protein–coupling specificities reveals unexpectedly diverse signaling pathways for individual GPCRs and their ligands.

In the hippocampus, inhibitory neurotransmitter GABA shapes activity of output pyramidal neurons and plays important role in cognition. Most its effects are mediated by signaling from GABAB receptor to G protein-gated Inwardly-rectifying K+ (GIRK) channels. Here, we show that RGS7, cooperation with binding partner R7BP, regulates GABABR-GIRK hippocampal neurons. Deletion RGS7 mice dramatically sensitizes GIRK responses stimulation markedly slows channel deactivation kinetics. Enhanced this...

Abstract Caspase-2 is the most evolutionarily conserved member in caspase family of proteases and constitutively expressed cell types including neurons; however, its physiological function remains largely unknown. Here we report that caspase-2 plays a critical role synaptic plasticity cognitive flexibility. We found deficiency led to deficits dendritic spine pruning, internalization AMPA receptors long-term depression. Our results indicate degrades Rictor, key mTOR complex 2 (mTORC2)...

P2X receptors (P2XRs) are ion channels gated by synaptically released ATP. The P2X4 is the most abundant P2XR subtype expressed in central nervous system and to date ethanol-sensitive. In addition, genomic findings suggest that P2X4Rs may play a role alcohol intake/preference. However, little known regarding how ethanol causes inhibition of ATP-gated currents P2X4Rs. We begin address this issue investigating effects wild-type mutant D331A M336A human embryonic kidney (HEK) 293 cells using...

ATP-gated P2X4 receptors (P2X4R) are abundantly expressed in the CNS. However, little is known about molecular targets for ethanol action P2X4Rs. The current investigation tested hypothesis that ectodomain-transmembrane (TM) interface contains residues important of Wild type (WT) and mutant P2X4R were Xenopus oocytes. ATP concentration-response curves (10-200 mM)-induced changes EC(10)-gated currents determined using two-electrode voltage clamp (-70 mV). Alanine substitution at...

The neuromodulatory effects of GABA on pyramidal neurons are mediated by B receptors (GABA Rs) that signal via a conserved G-protein-coupled pathway. Two prominent effectors regulated Rs include G-protein inwardly rectifying K + (GIRK) and P/Q/N type voltage-gated Ca 2+ (Ca V 2) ion channels control excitability synaptic output these neurons, respectively. Regulator signaling 7 (RGS7) has been shown to effects, yet the specificity its impacts effector underlying molecular mechanisms is...

The striatum plays a fundamental role in motor learning and reward-related behaviors that are synergistically shaped by populations of D1 dopamine receptor (D1R)- D2 (D2R)-expressing medium spiny neurons (MSNs). How various neurotransmitter inputs converging on common intracellular pathways parsed out to regulate distinct behavioral outcomes neuron-specific manner is poorly understood. Here, we reveal contributions D1R-MSNs D2R-MSNs towards reward delineated the multifaceted signaling...

Abstract Acid‐sensing ionic channels (ASICs) are involved in such functions of the sensory nervous system as mechanoreception, nociception and perception acid taste. Phe‐Met‐Arg‐Phe amide‐related (FMRFa‐related) peptides µ m concentrations slow down rate ASICs desensitization. Here we report that this effect is strongly pH dependent: lower used to activate ASICs, larger modulatory Arg‐Phe (RFa‐related) peptides. Pre‐application results a change desensitization kinetics ASICs‐operated current...

Analysis of long-term potentiation (LTP) provides a powerful window into cellular mechanisms learning and memory. Prior work shows late LTP (L-LTP), lasting >3 hr, occurs abruptly at postnatal day 12 (P12) in the stratum radiatum rat hippocampal area CA1. The goal here was to determine developmental profile synaptic plasticity leading L-LTP mouse hippocampus. Two strains two mutations known affect were chosen: C57BL/6J Fmr1-/y on background, 129SVE Hevin-/- (Sparcl1-/- ) background. Like...

Abstract RFamide (RFa)‐related peptides modulate pain processing in the mammalian CNS. The effects of these are generally considered as ‘anti‐opioid’. They also decrease rate desensitization acid‐sensing ionic channels (ASICs), putative nociceptors dorsal root ganglia neurons [C. Askwith et al . (2000) Neuron , 26 133–141]. We have tested role mollusc‐derived peptide, FMRFa (Phe‐Met‐Arg‐Phe‐amide) and its synthetic analogues peripheral nociception. Here we demonstrate that RFa‐related...

Ryanodine is a selective ryanodine receptor (RyR) blocker, with binding dependent on RyR opening. In whole-cell studies, can lock the in an open-conductance state, short-circuiting sarcoplasmic reticulum, which restricts studies of inositol-1,4,5-trisphosphate (InsP₃R) activity. Other blockers have nonselective effects that also limit their utility. 4-(2-Aminopropyl)-3,5-dichloro-<i>N</i>,<i>N</i>-dimethylaniline (FLA 365) blocks RyR-elicited Ca²⁺ increases skeletal and...

Analysis of neuronal compartments has revealed many state-dependent changes in geometry but establishing synapse-specific mechanisms at the nanoscale proven elusive. We co-expressed channelrhodopsin2-GFP and mAPEX2 a subset hippocampal CA3 neurons used trains light to induce late-phase long-term potentiation (L-LTP) area CA1. L-LTP was shown be specific labeled axons by severing inputs, which prevented back-propagating recruitment unlabeled axons. Membrane-associated tolerated...

The neonatal Fc receptor, FcRn, recycles immunoglobulin G (IgG), extending its half-life and serum concentration 1• Efgartigimod is a human IgG1 fragment, natural ligand of engineered for increased affinity FcRn 2• was designed to outcompete endogenous IgG, preventing recycling promoting lysosomal degradation without impacting production 2-5 o Targeted reduction all IgG subtypes No impact on IgM or IgA in albumin levels increase cholesterol 1.

Abstract Analysis of neuronal compartments has revealed many state-dependent changes in geometry but establishing synapse-specific mechanisms at the nanoscale proven elusive. We co-expressed channelrhodopsin2-GFP and mAPEX2 a subset hippocampal CA3 neurons used trains light to induce late-phase long-term potentiation (L-LTP) area CA1. L-LTP was shown be specific labeled axons by severing inputs, which prevented back-propagating recruitment unlabeled axons. Membrane-associated tolerated...

ABSTRACT Analysis of long-term potentiation (LTP) provides a powerful window into cellular mechanisms learning and memory. Prior work shows late LTP (L-LTP), lasting &gt;3 hours, occurs abruptly at postnatal day 12 (P12) in rat hippocampus. The goal here was to determine the developmental profile synaptic plasticity leading L-LTP mouse Two strains two mutations known affect were chosen: C57BL/6 Fmr1 −/y on background, 129SVE Hevin −/− ( Sparcl1 ) background. Like rats, hippocampal slices...

The endogenous opioid system is critical for natural reward responses that drive positive behavioral reinforcement, as well the reinforcing effects associated with addictive substances, such morphine. rewarding and properties of many drugs abuse depend on activation m‐opioid receptor (MOR). MOR a G‐protein coupled whose signaling efficiency controlled by regulator (RGS) proteins. In vitro studies have demonstrated RGS7, member R7 family RGS proteins, negatively regulates via inhibitory...