nAChR

[Nicotinic Acetylcholine Receptors Control Encoding and Retrieval of Associative Recognition Memory through Plasticity in the Medial Prefrontal Cortex] - encoding vs. retrieval paradigm 9-18-2021

Nicotinic Acetylcholine Receptor (nAChR) #

Two subtypes: N1 and N2. This division is really only relevant for physiology at large and not relevant to neuroscience, since N1/NM is only found in the PNS the Neuromuscular Junction on skeletal muscle, and N2 is found only in the CNS.
Topology of ligand binding sites on the nicotinic acetylcoline receptor
- After the vesicle content is spilled into the synaptic cleft the time course of neurotransmitter clearance is between 0.1 and 2.0 ms reaching concentrations of 1-5 mM.
[Selective coactivation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid–induced synaptic dysfunction]

Permeabilities are significantly altered depending on subunit structure: neuronal-types, especially receptors containing α7 have higher Ca2+ permeability.
I α9, α10
II: α7 nAChR, α8 (not in mammals)
III1: α2, α3, α4 nAChR, α6; III2: β2 nAChR, β4 nAChR; III3: β3, α5 nAChR
IV (muscle-type): α1, β1, δ, γ, ε. I believe this set are all exclusively for the α$_{2 \\ }$βγδ, becoming α${_2 \\ }$βγε post-embryonic.
All ‘cys-loop receptors’ form a central pore out of 5 subunits to create a pentamer ion channel.
α7 is the only widely distributed homomer in mammals, but α9 also forms one.
Each subunit spans the membrane four times:
- The M2 domain is non-competitively inhibited by Substance P, Serotonin, Progesterone, Testosterone, Glucocorticoids, and Anandamide.

Some of these I just kind of see. Dunno how important they are. But there’s hella subunits so imagine how many permutations of heteromers exist.

It seems the orthosteric binding sites are only located on the counterclockwise side of each α subunit, in the extracellular domain.
α4β2 nAChR = 2x of one, 3x of another.
α7β2 nAChR
α3β4 nAChR
α7 is low-affinity compared to α4β2.

While neuromuscular nAChRs mediate fast synaptic transmission, they are mostly slow in the CNS.
IT has been proposed that the majority of cortical/hippocampal cholinergic release sites are nonsynaptic and contribute to diffuse volume transmission, which
Prolonged exposure to nicotine leads to desensitization, stabilizing the ion channel to a closed state, unresponsive to agonism.
Presynaptic nAChR facilitates the release of other neurotransmitters while postsynaptic mediate and modulate ecitation within circuits and intracellular processes.
Agonists can improve mood/anxiety/aggression/cognition in depressed patients.
Stimulation increses dopamine concentration.
Inhibited by DHEA-S, T3, Pregnenolone, hydrocortisone.
- Although, DHEA-S activates the Sigma Receptor, promoting the release of ACh (and dopamine).
nAChR activation synergizes with AMPAR in reducing intracellular polarity, encouraging NMDAR activation.
- Interesting if true, as how does this relate to the pathology of Alzheimer’s?