Functional Selectivity
Encyclopedia
Functional selectivity (or “agonist trafficking”, “biased agonism”, “differential engagement” and “protean agonism”) is the ligand
-dependent selectivity for certain signal transduction
pathways in one and the same receptor
. This can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor.
.
Traditional pharmacology posits that a ligand
can be either classified as an agonist
(full or partial), antagonist
or more recently an inverse agonist
through a specific receptor subtype, and that this characteristic will be consistent with all effector
(second messenger
) systems coupled to that receptor. While this dogma has been the backbone of ligand-receptor interactions for decades now, more recent data indicates that this classic definition of ligand-protein associations does not hold true for a number of compounds.
Functional selectivity posits that a ligand may inherently produce a mix of the classic characteristics through a single receptor isoform depending on the effector pathway coupled to that receptor. For instance, a ligand can not easily be classified as an agonist or antagonist, because it can be a little of both, depending on its preferred signal transduction pathways. Thus, such ligands must instead be classified on the basis of their individual effects in the cell, instead of being either an agonist or antagonist to a receptor.
It is also important to note that these observations were made in a number of different expression systems and therefore functional selectivity is not just an epiphenomenon
of one particular expression system.
, as well as the 5-HT2C receptor
. Serotonin
, the main endogenous ligand of 5-HT receptor
s, is a functionally selective agonist at this receptor, activating phospholipase C
(which leads to inositol triphosphate
accumulation), but does not activate phospholipase A2
, which would result in arachidonic acid
signalling. However, the other endogenous compound Dimethyltryptamine
activates arachidonic acid signalling at the 5-HT2A receptor, as do many exogenous hallucinogens such as DOB
and LSD
. Notably, LSD
does not activate IP3 signalling through this receptor to any significant extent. This may explain why direct 5-HT2 agonists have psychedelic
effects, whereas compounds that indirectly increase serotonin signalling at the 5-HT2 receptors, such as SSRIs, generally do not.
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
-dependent selectivity for certain signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways in one and the same receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
. This can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor.
Functional vs. traditional selectivity
Functional selectivity has been proposed to broaden conventional definitions of pharmacologyPharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
.
Traditional pharmacology posits that a ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
can be either classified as an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
(full or partial), antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
or more recently an inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
through a specific receptor subtype, and that this characteristic will be consistent with all effector
Effector
Effector may refer to:*An actuator, in robotics*Effector , a music album by the Experimental Techno group Download*Effector cell, a type of lymphocyte in immunology...
(second messenger
Second messenger system
Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. They relay the signals of hormones like epinephrine , growth factors, and others, and cause some kind of change in the activity of the cell...
) systems coupled to that receptor. While this dogma has been the backbone of ligand-receptor interactions for decades now, more recent data indicates that this classic definition of ligand-protein associations does not hold true for a number of compounds.
Functional selectivity posits that a ligand may inherently produce a mix of the classic characteristics through a single receptor isoform depending on the effector pathway coupled to that receptor. For instance, a ligand can not easily be classified as an agonist or antagonist, because it can be a little of both, depending on its preferred signal transduction pathways. Thus, such ligands must instead be classified on the basis of their individual effects in the cell, instead of being either an agonist or antagonist to a receptor.
It is also important to note that these observations were made in a number of different expression systems and therefore functional selectivity is not just an epiphenomenon
Epiphenomenon
An epiphenomenon is a secondary phenomenon that occurs alongside or in parallel to a primary phenomenon.-Medicine:...
of one particular expression system.
Examples
One notable example of functional selectivity occurs with the 5-HT2A receptor5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
, as well as the 5-HT2C receptor
5-HT2C receptor
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
. Serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, the main endogenous ligand of 5-HT receptor
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
s, is a functionally selective agonist at this receptor, activating phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(which leads to inositol triphosphate
Inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
accumulation), but does not activate phospholipase A2
Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
, which would result in arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
signalling. However, the other endogenous compound Dimethyltryptamine
Dimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
activates arachidonic acid signalling at the 5-HT2A receptor, as do many exogenous hallucinogens such as DOB
DOB
DOB or Dob may refer to:*Dob, Domžale, village in Slovenia*Mounir Dob , Algerian football referee*Date of birth or birthday *2,5-dimethoxy-4-bromoamphetamine, Bromo-DMA, a psychedelic drug**Meta-DOB, related substance...
and LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
. Notably, LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
does not activate IP3 signalling through this receptor to any significant extent. This may explain why direct 5-HT2 agonists have psychedelic
Psychedelic
The term psychedelic is derived from the Greek words ψυχή and δηλοῦν , translating to "soul-manifesting". A psychedelic experience is characterized by the striking perception of aspects of one's mind previously unknown, or by the creative exuberance of the mind liberated from its ostensibly...
effects, whereas compounds that indirectly increase serotonin signalling at the 5-HT2 receptors, such as SSRIs, generally do not.