The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies...

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Mammalian nicotinic acetylcholine receptors: from structure to function.

Since the rediscovery of transcranial direct current stimulation (tDCS) about 10 years ago, interest in tDCS has grown exponentially. A noninvasive stimulation technique that induces robust excitability changes within the stimulated cortex, tDCS is increasingly being used in proof-of-principle and stage IIa clinical trials in a wide range of neurological and psychiatric disorders. Alongside these clinical studies, detailed work has been performed to elucidate the mechanisms underlying the observed effects. In this review, the authors bring together the results from these pharmacological, neurophysiological, and imaging studies to describe their current knowledge of the physiological effects of tDCS. In addition, the theoretical framework for how tDCS affects motor learning is proposed.

Physiological Basis of Transcranial Direct Current Stimulation

Subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) are constructed from numerous subunit combinations that compose channel-receptor complexes with varied functional and pharmacological characteristics. Structural and functional diversity and the broad presynaptic, postsynaptic, and nonsynaptic locations of nAChRs underlie their mainly modulatory roles throughout the mammalian brain. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, postsynaptic nAChRs contribute a small minority of fast excitatory transmission, and nonsynaptic nAChRs modulate many neurotransmitter systems by influencing neuronal excitability. Nicotinic receptors have roles in development and synaptic plasticity, and nicotinic mechanisms participate in learning, memory, and attention. Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to dysfunctions such as epilepsy, schizophrenia, Parkinson's disease, autism, dementia with Lewy bodies, Alzheimer's diseas...

Nicotinic Acetylcholine Receptors and Nicotinic Cholinergic Mechanisms of the Central Nervous System

Nova proteins are neuron-specific antigens targeted in paraneoplastic opsoclonus myoclonus ataxia (POMA), an autoimmune neurologic disease characterized by abnormal motor inhibition Nova proteins regulate neuronal pre-messenger RNA splicing by directly binding to RNA To identify Nova RNA targets, we developed a method to purify protein-RNA complexes from mouse brain with the use of ultraviolet cross-linking and immunoprecipitation (CLIP)Thirty-four transcripts were identified multiple times by Nova CLIPThree-quarters of these encode proteins that function at the neuronal synapse, and one-third are involved in neuronal inhibitionSplicing targets confirmed in Nova-/- mice include c-Jun N-terminal kinase 2, neogenin, and gephyrin; the latter encodes a protein that clusters inhibitory gamma-aminobutyric acid and glycine receptors, two previously identified Nova splicing targetsThus, CLIP reveals that Nova coordinately regulates a biologically coherent set of RNAs encoding multiple components of the inhibitory synapse, an observation that may relate to the cause of abnormal motor inhibition in POMA

https://science.sciencemag.org/content/sci/302/5648/1212.full.pdf

CLIP identifies Nova-regulated RNA networks in the brain.

http://www.med.upenn.edu/ngg/user_docs/Picciotto.Neuron_ACh.pdf

Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior

https://www.cell.com/neuron/pdf/S0896-6273(01)00332-4.pdf

Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity.

Timing and Location of Nicotinic Activity Enhances or Depresses

The nucleus accumbens (NAc) of the ventral striatum is involved in attention, motivation, movement, learning, reward, and addiction. GABAergic medium spiny projection neurons that make up ∼90% of t...

https://www.physiology.org/doi/pdf/10.1152/jn.00066.2004

Complex response to afferent excitatory bursts by nucleus accumbens medium spiny projection neurons.

AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor's ligand-binding domains (LBDs) leads to ion channel activation and desensitization. Gating kinetics shape synaptic transmission and are strongly modulated by transmembrane AMPAR regulatory proteins (TARPs) through currently incompletely resolved mechanisms. Here, electron cryo-microscopy structures of the GluA1/2 TARP-γ8 complex, in both open and desensitized states (at 3.5 Å), reveal state-selective engagement of the LBDs by the large TARP-γ8 loop ('β1'), elucidating how this TARP stabilizes specific gating states. We further show how TARPs alter channel rectification, by interacting with the pore helix of the selectivity filter. Lastly, we reveal that the Q/R-editing site couples the channel constriction at the filter entrance to the gate, and forms the major cation binding site in the conduction path. Our results provide a mechanistic framework of how TARPs modulate AMPAR gating and conductance. 

/pdf/mechanisms-underlying-tarp-modulation-of-the-glua1-2-g8-ampa-3gku7cpn.pdf

Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor

/pdf/mechanisms-underlying-tarp-modulation-of-the-glua1-2-g8-ampa-1674w0j4.pdf

Remigijus Lape

Papers

Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity.

Timing and Location of Nicotinic Activity Enhances or Depresses

Complex response to afferent excitatory bursts by nucleus accumbens medium spiny projection neurons.

Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor

Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor