nAChR
ACh receptors are divided into two major classes, nicotinic ACh receptors (nAChRs) and muscarinic Ach receptors (mAChRs). nAChRs are highly expressed in skeletal muscle and the nervous system.nAChRs are classified as members of the cysteine-loop (Cys-loop) family of ligandgated ion channels. Subtypes of nAChRs can be classified based on the predominant α-subunits (α1–α10) because the α subunit plays a key role in agonist binding to trigger ion channel opening, and subtype-selective antagonists like α-bungarotoxin distinguish receptors based on the α subunit combination. Recently, expression of nAChRs in immune cells and glial cells has also attracted attention for potential therapeutic targeting in inflammation and neurodegenerative diseases. nAChRs are grouped into muscle-type (Nm), peripheral neuronal-type (Nn), and central neuronal-type (CNS) based on their distribution, subunit composition, and selective antagonists. In all types of nAChRs, agonists such as ACh itself or nicotine-induced ion channel opening and evoke influx of Na+ and Ca2+.
This triggers cell depolarization and turns on various functional switches. Nicotinic cholinergic responses correlated with fast neurotransmission are easily detected in the endplate at the neuromuscular junction and ganglion cells of the sympathetic nerves. In the cerebral cortex, persistent nAChR stimulation triggers signals to the phosphoinositide 3-kinase (PI3K) cascade, which contributes to neuroprotection. nAChRs, especially α7 nAChRs, generate specific and complex Ca2+ signals that include adenylyl cyclase, protein kinase A, protein kinase C, Ca2+-calmodulin-dependent kinase, and phosphatidylinositol 3-kinase (PI3K). These phosphorylated downstream targets activate cellular signaling related to exocytosis and extracellular signal-regulated mitogen-activated protein kinase (ERK)-linked neuronal functions. The intracellular signal pathway downstream of CNS nAChRs is known as a major pathway of neuroprotective action of neurotrophins including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NGF and BDNF are known to affect survival and differentiation of central and peripheral neurons.
References
1.Akaike A, et al. Springer; 2018:1–15.
This triggers cell depolarization and turns on various functional switches. Nicotinic cholinergic responses correlated with fast neurotransmission are easily detected in the endplate at the neuromuscular junction and ganglion cells of the sympathetic nerves. In the cerebral cortex, persistent nAChR stimulation triggers signals to the phosphoinositide 3-kinase (PI3K) cascade, which contributes to neuroprotection. nAChRs, especially α7 nAChRs, generate specific and complex Ca2+ signals that include adenylyl cyclase, protein kinase A, protein kinase C, Ca2+-calmodulin-dependent kinase, and phosphatidylinositol 3-kinase (PI3K). These phosphorylated downstream targets activate cellular signaling related to exocytosis and extracellular signal-regulated mitogen-activated protein kinase (ERK)-linked neuronal functions. The intracellular signal pathway downstream of CNS nAChRs is known as a major pathway of neuroprotective action of neurotrophins including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NGF and BDNF are known to affect survival and differentiation of central and peripheral neurons.
References
1.Akaike A, et al. Springer; 2018:1–15.
Membrane Transporter/Ion Channel
AMPK(58)
ASBT Transporter(6)
BCRP(10)
Beta Amyloid(69)
Carbonic Anhydrase(40)
Chloride Channel(34)
CRAC Channel(0)
CRM1(5)
Exportin-1(5)
FABP(6)
GAT(63)
GLUT(5)
Glutamate Transporter(1)
GlyT(13)
HCN Channel(5)
iGluR(52)
Monoamine Transporter(26)
Monocarboxylate Transporter(12)
MTP(1)
nAChR(5)
NADPH(35)
Na-K-ATPase(2)
NKCC(4)
NMDAR(65)
OCT(4)
Other Targets(13)
P2X Receptor(23)
P-glycoprotein(14)
Proton Pump(38)
Sodium Channel(147)
TRP/TRPV Channel(115)
URAT1(1)
nAChR
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JNJ-39393406
catalog no : M16813
cas no: 953428-73-4
JNJ-39393406 is a potent, selective positive allosteric α7 nAChR modulator, potentiates a 100 μM choline-induced rise in intracellular calcium mediated by human α7 channels expressed in GH4C1 cells with EC50 of 660 nM. -
ZSET1446
catalog no : M16417
cas no: 887603-94-3
A small molecule cognitive enhancer that potentiates acetylcholine-mediated facilitation of inhibitory synaptic transmission in the hippocampal neurons. -
AQW-051
catalog no : M15558
cas no: 669770-29-0
AQW-051 is a novel, potent and selective, orally bioavailable, brain-penetrant α7 nAChR partial agonist with pKd of 7.56. -
Galanthamine
catalog no : M14230
cas no: 357-70-0
A potent allosteric potentiating ligand of human nAChRs α4β2, α3β4, and α6β4; potentiates agonist responses of the four nAChR subtypes at 0.1-1 uM. -
Nelonicline
catalog no : M10124
cas no: 1026134-63-3
Nelonicline (ABT-126) is a potent, selective α7 nicotinic receptor (nAChR) partial agonist for the treatment of cognitive impairment with schizophrenia.