A receptor is a biological molecule that binds to a ligand and produces effects. Many types of receptors are present in human body. Some receptors are coupled with enzymes. Others are enzymes themselves. Some receptors are linked to some GTP coupled proteins.
All these receptors require some second messenger to carry out their response. In midst of all these receptors is a special type of receptors that do not require any second messenger system. They are the ionotropic receptors.
Ionotropic receptors are coupled with some ion channels. When they bind a ligand, activation of the receptor results in a conformational change, rendering the ion channel open. In other words, they are the ligand-gated ion channels. Binding of the ligand results in the opening of ion channels.
In this article, we will discuss the general structure of an ionotropic receptor. We will also discuss some important types of ionotropic receptors in the body, their location, and clinical significance, along with their role in the body. We will discuss drugs affecting different ionotropic receptors and their clinical significance.
The ionotropic receptors are the transmembrane proteins often referred to as ligand-gated ion channels. These are the ion channels that allow the diffusion of ions down the concentration gradient. This diffusion is facilitated by some ligand that binds to the receptor and opens the ion channels.
These receptors are often composed of more than one subunit. The ligand binds to one or more subunits, resulting in a conformational change that opens the ion channels. As a result, ions rush in or out of the cell down their concentration gradient.
Now we will talk about some important ionotropic receptors present in the body.
Nicotinic Acetylcholine Receptors
These are the ionotropic receptors present in the neuromuscular junction. They are made up of five subunits arranged in the form of staves around a barrel. These are two α, one β, one ɛ, and one δ subunits. The acetylcholine binds to one of the α subunit, which increases the affinity of other α subunit.
When both α subunits are occupied by the acetylcholine, it causes a conformational change that results in the opening of ion channels. These ion channels allow the sodium and potassium ions to diffuse down the concentration gradient. They are therefore called the cation channels.
They are present in the postjunctional fold of sarcolemma, a part of neuromuscular junction.
They cause the excitation of the skeletal muscle. They allow the nerve impulse to be passed from the motor neuron to the skeletal muscle fibers.
The activity of nicotinic receptors is affected by cholinergic drugs and neuromuscular blockers.
The cholinergic drugs enhance the activity by increasing the amount of acetylcholine available to activate the receptor. These include direct-acting drugs such as methacholine and indirect-acting drugs such as nerve gas.
Neuromuscular blockers, as the name suggests, block the activity of these receptors. They do so either by antagonizing the receptors or by causing increased depolarization and A1 block.
Myasthenia Gravis is an important clinical condition associated with nicotinic receptors. It is an autoimmune disease in which antibodies are formed against the nicotinic receptors. It results in generalized muscle weakness, which most severely affects the muscles of eyes and pharynx.
These are important ionotropic receptors present in the CNS. They are the main inhibitory receptors in the CNS. They are made up of five subunits. Binding of GABA neurotransmitter to one of the subunit results in the opening of the ion channels. These receptors are classified into two types on the basis of ionic specificity. These are GABAA and GABAB receptors.
GABAA receptors are linked to Cl– channels. When a molecule of GABA binds to this receptor, it causes the opening of the Cl– channels. As the concentration of Cl– ions is higher in the extracellular fluid, the Cl– ions flow inside the cell decreasing the membrane potential, thus causing hyperpolarization.
Although these receptors cause opening of K+ channels, GABAB receptors are linked to G-proteins and are not purely ionotropic receptors.
These receptors are present on the neurons within the brain.
These are the main inhibitory receptors present in the brain. Activation of these receptors decreases neuronal firing. They play an important role in calming a person, inducing sleep and relieving anxiety.
Most of the CNS depressants act via GABA receptors. Most of these drugs potentiate the effects of GABA on these receptors.
Barbiturates such as secobarbital, phenobarbital, etc. act on GABAA receptor and increase the duration of open Cl– channel.
Benzodiazepines, used to relieve anxiety and insomnia, also act on GABAA receptor and increase the frequency of opening of Cl– channels.
Alcohol also potentiate GABA at GABAA receptors.
These are excitatory neurotransmitters present in CNS. They are made up of four subunits. Each subunit further consists of three domains; amino-terminal domain, ligand-binding domain, and a transmembrane domain.
The amino-terminal domain is important for the structural stability of the receptor. The ligand-binding domain, as the name suggests, binds the ligand or glutamate neurotransmitter. Both these domains are extracellular domains. The third one is a transmembrane domain that forms the ion channel. Together, all these four subunits form a tetramer.
As the ligand-binding domain is a part of every subunit, only two of these domains are needed to be occupied by the glutamate neurotransmitter in order to open the ion channel.
The ion channel, when open, allows the entry of calcium ions into the cell. This diffusion of positive ions within the cell causes depolarization resulting in action potential. This is the reason why glutamate receptors are excitatory receptors.
Depending on the type of agonists they bind, glutamate receptors are of two types, AMPA receptors and NMDA receptors.
The glutamate receptors are the most commonly found receptors in the brain. They are the main excitatory receptors of the CNS. The NMDA type receptors are also responsible for regulating synaptic plasticity and memory.
The drugs acting on glutamate receptors can be divided into two categories, agonists and antagonists.
The agonists at the APMA and NMDA receptors are different.
The agonists at APMA include glutamate, AMPA, 5-Fluorowillardiine, Domoic acid and Quisqualic acid, etc.
The agonists at NMDA receptors include glutamate, D-cycloserine, glycine, and quinolinate, etc.
The antagonists at two types of receptors are also different.
The antagonists at NMDA include ketamine, PCP, tramadol, kynurenic acid, etc.
The antagonists at the AMPA receptors are Kynurenic acid, Perampanel, etc.
Serotonin 5-HT3 Receptors
These are the only serotonin ionotropic receptors present in the chemoreceptor trigger zone. The bind to endogenous serotonin and cause opening of the ion channels. These ion channels are permeable to sodium, potassium and calcium ions.
The activation of these channels initiates the process of depolarization and an action potential is generated. The resultant effect is activation of CTZ neurons and emesis occurs.
These receptors trigger the process of emesis.
The clinically significant drugs are the serotonin 5-HT3 selective antagonist. These include ondansetron, granisetron, and other “setrons” drugs. These are important anti-emetic drugs.
The antagonists of these drugs are used as anti-emetic drugs. They are commonly used to prevent vomiting in chemotherapy and post-radiotherapy medication.
ATP Gated Receptors
These are also called P2X receptors. They consist of two transmembrane domains that form the ion channels and an extracellular domain. The extracellular domain acts as a ligand-binding domain.
The binding of ATP to this domain results in the opening of the ion channel. These ion channels allow the entry of calcium channels within the cell. As a result, depolarization occurs, and action potential is generated.
The ATP or P2X receptors perform several important functions. These include the following;
- Regulation of cardiac rhythm and heart rate
- Regulation of blood vessel tone
- Platelet aggregation
- Contraction of Vas Deferens for ejaculation
- Contraction of bladder for micturition
Ionotropic receptors are actually ligand-gated ion channels. They are the only receptors that do not require a second messenger and show immediate effects. The effects of such receptors are immediate and are very short-lived.
Depending upon their subunits and location, they allow different ions to diffuse down the concentration gradient. They may be excitatory or inhibitory receptors.
The important ionotropic receptors are the following.
Nicotinic receptors: They are present in the neuromuscular junction. They are the excitatory receptors responsible for skeletal muscle contraction.
GABA receptors: They are the most common inhibitory receptors present in the CNS. They are responsible for sedation, sleep and anesthesia.
Glutamate receptors: They are the most abundant excitatory receptors in the CNS.
5-HT3 receptors: These are the ionotropic serotonin receptors present in the chemoreceptor trigger zone. They are responsible for causing emesis.
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