Muscarinic acetylcholine receptor M4
Encyclopedia
The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein
that, in humans, is encoded by the CHRM4 gene
.
s belong to a larger family of G protein-coupled receptor
s. The functional diversity of these receptors is defined by the binding of acetylcholine
and includes cellular responses such as adenylate cyclase
inhibition, phosphoinositide degeneration, and potassium channel
modulation. Muscarinic receptors mediate many effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor are unknown; however, mouse studies link its function to adenylyl cyclase inhibition.
M4 muscarinic receptors function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine
release in the striatum
. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus
and cerebral cortex
.
Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic
neurotransmission
. Activation of M4 receptors in the striatum
inhibit D1-induced locomotor stimulation in mice
. M4 receptor-deficient mice exhibit increased locomotor simulation in response to D1 agonist
s, amphetamine
and cocaine
. Neurotransmission in the striatum influences extrapyramidal
motor control
, thus alterations in M4 activity may contribute to conditions such as Parkinson's Disease
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that, in humans, is encoded by the CHRM4 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
The muscarinic cholinergic receptorMuscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s belong to a larger family of G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s. The functional diversity of these receptors is defined by the binding of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
and includes cellular responses such as adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
inhibition, phosphoinositide degeneration, and potassium channel
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
modulation. Muscarinic receptors mediate many effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor are unknown; however, mouse studies link its function to adenylyl cyclase inhibition.
M4 muscarinic receptors function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
release in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
.
Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
. Activation of M4 receptors in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
inhibit D1-induced locomotor stimulation in mice
MICE
-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...
. M4 receptor-deficient mice exhibit increased locomotor simulation in response to D1 agonist
Dopamine agonist
A dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...
s, amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
and cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
. Neurotransmission in the striatum influences extrapyramidal
Extrapyramidal
Extrapyramidal can refer to:* Extrapyramidal system* Extrapyramidal symptoms...
motor control
Motor control
Motor control are information processing related activities carried out by the central nervous system that organize the musculoskeletal system to create coordinated movements and skilled actions...
, thus alterations in M4 activity may contribute to conditions such as Parkinson's Disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Antagonists
- AFDX-384AFDX-384AFDX-384 is a drug which acts as a selective antagonist of the muscarinic acetylcholine receptors, with selectivity for the M2 and M4 subtypes. It is used mainly for mapping the distribution of M2 and M4 muscarinic receptors in the brain, and studying their involvement in the development and...
(mixed M2/M4 antagonist, N-[2-[2-[(Dipropylamino)methyl]-1-piperidinyl]ethyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide, CAS# 118290-27-0) - Dicycloverine
- HimbacineHimbacineHimbacine is an alkaloid isolated from the bark of Australian magnolias. Himbacine has been synthesized using a Diels-Alder reaction as a key step. Himbacine's activity as a muscarinic receptor antagonist, with specificity for the Muscarinic acetylcholine receptor M2, made it a promising starting...
- Mamba toxin 3
- PD-102,807PD-102,807PD-102,807 is a drug which acts as a selective antagonist for the muscarinic acetylcholine receptor M4. It is used in scientific research for studying the effects of the different muscarinic receptor subtypes in the body and brain....
(3,6a,11,14-Tetrahydro-9-methoxy-2-methyl-(12H)-isoquino[1,2-b]pyrrolo[3,2-f][1,3]benzoxazine-1-carboxylic acid ethyl ester, CAS# 23062-91-1) - PD-0298029PD-0298029PD-0298029 is a drug which acts as a selective antagonist for the muscarinic acetylcholine receptor M4. It was developed for the treatment of Parkinson's disease, but poor bioavailability and rapid metabolism in animal studies have meant its use is largely limited to in vitro research into the M4...
- TropicamideTropicamideTropicamide is an anticholinergic used as a mydriatic. In Russia, it is used to some degree as an inexpensive recreational drug...
- moderate selectivity over other muscarinic subtypes (2-5x approx)