The human muscarinic acetylcholine receptor M
5, encoded by the gene, is a member of the
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
superfamily of
integral membrane protein
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a signi ...
s. It is coupled to G
q protein.
Binding of the
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
to the M
5 receptor triggers a number of cellular responses such as
adenylate cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
inhibition,
phosphoinositide
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
degradation, and
potassium channel
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease
cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
levels and downregulate the activity of protein kinase A (PKA).
Ligands
No highly selective agonists or antagonists for the M
5 receptor have been discovered as of 2018, but several non-selective muscarinic agonists and antagonists have significant affinity for M
5.
The lack of selective M5 receptor ligands is one of the main reasons that the medical community has such a limited understanding of the M5 receptors effects as the possibility that any and/or all effects of non-selective ligands may be due to interactions with other receptors can not be ruled out. Some data may be obtained by observing which effects are common among semi-selective ligands (ex. a ligand of M1 and M5, a ligand of M2 and M5, and a ligand of M3 and M5), but until both a selective agonist and a selective antagonist of the M5 receptor are developed this data must be considered merely theoretical.
Agonists
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Milameline
Milameline (CI-979, PD-129,409, RU-35,926) is a non-selective muscarinic acetylcholine receptor partial agonist with cognition-acting properties that was being investigated for the treatment of Alzheimer's disease, but produced poor results in cl ...
((E)-1,2,5,6-Tetrahydro-1-methyl-3-pyridinecarboxaldehyde-O-methyloxime, CAS# 139886-32-1)
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Sabcomeline
Sabcomeline (Memric; SB-202,026) is a selective M1 receptor partial agonist that was under development for the treatment of Alzheimer's disease. It made it to phase III clinical trial
Clinical trials are prospective biomedical or behaviora ...
Positive allosteric modulators
* ML-380
* ML-326
*
VU-0238429
VU-0238429 is a drug which acts as a selective positive allosteric modulator
In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, ...
:
EC50 = 1.16 μM; >30-fold selectivity versus M1 and M3, inactive at M2 and M4.
Negative allosteric modulators
*
ML375
*VU6008667
Antagonists
* VU-0488130 (ML381)
*
Xanomeline
Xanomeline (LY-246,708; Lumeron, Memcor) is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatme ...
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Diphenhydramine
Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected into a vein ...
See also
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Muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rece ...
References
Further reading
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{{DEFAULTSORT:Muscarinic Acetylcholine Receptor M5
G protein-coupled receptors
Human proteins
Muscarinic acetylcholine receptors