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Receptors

Introduction to receptors

Receptors are the biochemical structures that bind to specific ligands and produce cellular responses. Receptors are usually proteins and ligands are the chemical substances that bind to the receptor. When a ligand binds to the receptor, a cellular response is produced which may take several forms such as alterations in the gene transcription or translation, changes in membrane permeability, opening or closing of specific ion channels, production and release of specific granules, etc. The ligand which binds the receptor may be an ion, molecule, peptide, drug, or toxin. One receptor may bind to different ligands and produce different responses. Similarly, one ligand may produce different responses while acting on different receptors. The response also varies depending on the signaling cascade. For example, histamine acts on H1, H2, H3, and H4 receptors. On H1 receptors it acts through the Gq pathway and increases vessel permeability, on H2 receptors its action is via the Gs pathway and increases cAMP while on H3 and H4 receptors, histamine action is produced through the Gi pathway decreasing cAMP.

Classification of receptors

We can classify receptors on the basis of their mechanism of action or the type of molecule or stimulus they detect. Some receptors may even produce a response without any ligand such as stretch receptors in the walls of blood vessels. Classification of receptors is wide and can’t be covered under a single title. Some general classifications of receptors are as under.

Classification of receptors on the basis of their mechanism

On the basis of mechanism receptors are as under:

Intracellular receptors

These are the receptors located inside the cell. They may be found in the cell cytoplasm or nucleus and bind to different hormones, steroids, cytokines, and growth factors and play a crucial role in cell signaling and gene expression. Intracellular receptors are further classified into ligand-gated receptors and ligand-regulated receptors. Ligand-gated receptors undergo conformational change on binding to the ligand while ligand-gated receptors are the receptors whose activity either decreases or increases on binding the ligand. Intracellular receptors are involved in regulating cell growth, differentiation, immune response, and regulation of metabolic pathways. They are also involved in the pathology of several inflammatory disorders and various types of cancers. Examples of intracellular receptors include cytokine receptors which mediate immune response, thyroid hormone receptors which alter the metabolic rate, and steroid hormone receptors which bind to specific DNA sequences and regulate gene expression.

Membrane receptors coupled directly to ion channels

Illustration showing membrane receptors
Illustration showing a membrane receptor

These are this specific receptors located on the cell membrane and are linked to the specific ion channels. They are proteins that facilitate the movement of specific ions across the plasma membrane. They have a large membrane-spanning domain which enables them to act as an ion channel. When a ligand binds to these ion channels coupled receptors, they undergo conformational change and open the specific channel affecting the excitability of the target cell. The channel they open can be cationic or anionic. Depending upon whether the opened channel is cationic or anionic, these receptors can be depolarizing or hyperpolarizing receptors. If they open the sodium channel sodium enters into the cell cytoplasm and increases the membrane potential, so the cell is depolarized. If they open the potassium channel, potassium leaves the cell, and the cell is hyperpolarized as negativity inside the cell increases due to the loss of positive ions. If these receptors open anionic channels cell is hyperpolarized as negatively charged ions especially chloride will enter from extracellular space into the cell increasing the negative potential. 

Examples of ion channel-linked receptors include nicotinic receptors, glutamate receptors, and GABA A receptors. Nicotinic receptors are found in the autonomic ganglia, adrenal medulla, and neuromuscular junction and are linked to Na/K channels. They increase the excitability of cells due to increased cationic conductance in the cell. Glutamate is the excitatory neurotransmitter in the brain that opens sodium channels and depolarizes the cells.

GABA is the inhibitory neurotransmitter in the brain. GABA A receptors produce the inhibitory response by opening the chloride ion channels. Due to the influx of chloride ions, the cell is hyperpolarized and its excitability is greatly reduced. The receptors which are linked to ion channels are called ionotropic receptors.

G protein-coupled receptors

G protein-coupled receptors are the specific receptors coupled to G proteins. They are also called metaboreceptors. They have an extracellular ligand binding domain, 7 transmembrane domains, and an intracellular G-protein binding domain. They produce a secondary messenger’s cascade which produces the cellular response. G protein binds GDP in its inactivated state. When the receptor binds to the ligand, G protein releases ADP and binds to GTP which in turn produces a response. G protein can be Gq, Gs, or Gi.

Gq pathway

In the Gq pathway, a ligand binds to the receptor and activates it. The intracellular domain interacts with the Gq protein which releases GDP and binds to GTP. The alpha subunit of the Gq protein dissociates and activates the phospholipase C enzyme which cleaves phosphatidyl-inositol bisphosphate to inositol triphosphate and diacylglycerol. Inositol triphosphate binds to specific receptors on the endoplasmic reticulum and causes the release of stored calcium ions. Calcium and diacylglycerol activate protein kinase C which phosphorylates specific proteins producing the cellular response. Several hormones produce response through Gq coupled receptors such as angiotensin II (on vascular smooth muscles), parathyroid hormone, oxytocin, thyrotropin-releasing hormone, growth hormone-releasing hormone,  catecholamines (alpha 1 adrenergic receptors), vasopressin (V 1 receptors), etc.

Gs pathway

In the Gs pathway, the Gs protein is activated when a ligand binds to the receptor. The alpha subunit of the Gs protein activates adenylate cyclase which increases the production of cAMP. cAMP activates protein kinase A which phosphorylates multiple proteins and produces a cellular response. Examples of Gs-coupled receptors include receptors for the adrenocorticotropic hormone, angiotensin II (epithelial cells), calcitonin, catecholamines (beta receptors), corticotropin-releasing hormone, glucagon, growth hormone-releasing hormone, human chorionic gonadotropin, secretin, luteinizing hormone, etc.

Gi pathway

Stimulation of Gi proteins decreases the production of cAMP and reduces cellular response. Alpha 2 adrenergic receptors, opioid receptors, and serotonin receptors subtypes are Gi-coupled.

Receptors functioning as tyrosine kinase

These are the receptors having an extracellular domain that binds ligands and an intracellular domain that functions as tyrosine kinase and phosphorylates specific substrates to produce the response. Examples of such receptors include insulin receptors, epidermal growth factor receptors, and platelet-derived growth factor receptors. The functioning of the insulin receptors is well established. The insulin receptor has two alpha and two beta subunits. Insulin molecule binds to the extracellular alpha subunits which activate the tyrosine kinase activity of the intracellular domain of beta subunits which are autophosphorylated. Tyrosine kinase also phosphorylates other proteins such as insulin receptor substrates. Phosphorylation of insulin receptor substrate promotes the activity of other kinases and phosphatases inside the cell producing metabolic effects of insulin.

Receptors linked to tyrosine kinases

Some receptors don’t have intrinsic tyrosine kinase activity. Instead, they are linked to other intracellular tyrosine kinases which produce their response. Examples of such receptors include erythropoietin, leptin, and interferon receptors. When a ligand (e.g. leptin) binds to the receptor there is a conformational change in receptors which activates specific tyrosine kinase of the Janus kinase family. Activated tyrosine kinase of the Janus Kinase family phosphorylates “signal transducer and activation of transcription proteins” (STAT proteins). Phosphorylated STAT proteins move to the nucleus of the cell and bind to specific DNA regulatory sequences and alter gene expression.

Physiological classification of receptors

The physiological classification of receptors is based on the type of molecules or stimuli which activate the receptors. The physiological classification of receptors is as under:

Hormonal receptors

Hormonal receptors are receptors activated by hormones. These hormones act through different receptors and produce different responses. If the receptor or signaling mechanism of a hormone is impaired, the physiological function of the hormone is lost. Hormonal receptors may be intracellular receptors, directly linked to ion channels, G protein-coupled receptors, intrinsic tyrosine kinase receptors, or linked to tyrosine kinase receptors. Thyroid hormone receptors and glucocorticoid receptors are the intercellular receptors that bind to specific DNA sequences and alter gene transcription. Hormones acting through G protein-coupled receptors include thyroid stimulating hormone, glucagon, catecholamines, luteinizing hormone, parathyroid hormone, etc. Hormones acting through tyrosine kinase and tyrosine kinase-linked receptors include leptin and insulin etc.

Autonomic receptors

Autonomic receptors are the receptors involved in the sympathetic and parasympathetic nervous systems. The receptors involved in the parasympathetic nervous system are called cholinergic receptors as they respond to acetylcholine. They include muscarinic and nicotinic receptors. The receptors of the sympathetic nervous system are called adrenergic receptors as they respond to adrenaline and norepinephrine. They include alpha and beta receptors. Their distribution and responses vary in different body parts.

Cholinergic receptors

Cholinergic receptors (muscarinic and nicotinic receptors) are stimulated by acetylcholine which is released at the postsynaptic parasympathetic nerve fibers. Muscarinic receptors are further classified into M1, M2, and M3 receptors. M1 and M3 are Gq coupled while M2 is a Gi-coupled receptor. M1 is found in glands of GIT and increases secretions. M2 is found in sinoatrial and atrioventricular nodes and decreases heart rate and conduction velocity upon stimulation. M3 has a wide distribution. It is present in the sphincter of the iris and ciliary muscles where it produces miosis and accommodation to near vision. It’s present in bronchioles where it causes bronchospasm and increases glands’ secretions. M3 stimulation in GIT increases motility, in the bladder it causes contraction of the detrusor muscle and relaxation of the trigone and sphincter to promote urination, in blood vessels M3 stimulation causes vasodilation. M3 stimulation is also found to increase sweating, salivation, and lacrimation. Nicotinic receptors are found in the autonomic ganglia, adrenal medulla, and neuromuscular junction. They are directly linked to Na/K ion channels. Their stimulation causes generalized ganglionic activation, catecholamine release, and muscle twitching & increased contractility.

Adrenergic receptors

Adrenergic alpha receptors have further alpha-1 and alpha-2 subtypes. Alpha-1 receptors are found in the radial muscles of the eyes where they bring about mydriasis. In arterioles and veins, alpha-1 activation causes vasoconstriction increasing preload and afterload. Alpha-1 stimulation in the bladder and trigone causes urinary retention while in vas deference their stimulation causes ejaculation. Alpha-1 stimulation also decreases the renin release from the kidneys. Alpha-2 stimulation causes platelet aggregation, decreased insulin, and norepinephrine secretion. Beta-1 is present in the sinoatrial node, atrioventricular node, atrial and ventricular musculature, and kidneys. Its stimulation causes an increase in heart rate, conduction velocity, myocardial contractility, and renin secretion. Beta-2 receptors are mostly non-innervated and are found in blood vessels, the uterus, and bronchioles where they cause muscle relaxation. However, they increase insulin release from pancreatic beta cells.

Immune receptors

Illustration of immune receptors
Illustration of immune receptors

These are the receptors that detect antigens and dead cell products and trigger an immune response. These include Toll-like receptors, NOD-like receptors, C-type lectin receptors, collectin receptors, etc. Toll-like receptors are named so due to their association with the toll gene 1st discovered in drosophila. They are present on the cell surface as well as on endosomes in phagocytes and dendritic cells. The cell surface receptors detect microbial proteins and antigens while receptors on endosomes detect microbial DNA and RNA. Recognition of microbial products by Toll-like receptors activates many transcription factors which stimulate the production of various cytokines and inflammatory mediators and produce an immune response. NOD-like receptors are the cytosolic receptors that detect products of necrotic cells such as ATP, uric acid, ion disturbance, and microbial products. They activate a signaling pathway involving a cytosolic multiprotein complex called inflammasome which activates an enzyme caspase 1. Caspase 1 cleaves the precursor form of interleukin 1 to form active IL-1. IL-1 is involved in immune processes and inflammatory response. The gain of function mutations in the inflammasome pathway leads to auto-inflammatory disorders which are treated with interleukin -1 antagonist. Lectin and collectin receptors are the circulating proteins that detect bacterial products and activate the immune response.

Muscle receptors

Proper control of muscle contractions not only requires motor stimulation from the CNS but also continuous feedback of sensory information to regulate the strength of contraction. To provide this feedback control muscles and tendons are supplied with two kinds of receptors, muscle spindles, and Golgi tendon organs. Muscle spindles comprise a few intrafusal fibers in the muscle belly. The central portion of these intrafusal fibers contains little or no contractile proteins. Therefore their central portion doesn’t contract when the ends of fibers contract; instead, it acts as a sensory receptor and gets excited when it’s stretched by extrafusal fibers or ends of intrafusal fibers. This stretching generates signals in the primary and secondary afferents supplying the muscle spindles which convey messages to the CNS which regulates the muscles’ contractility. The Golgi tendon organ is an encapsulated sensory ending through which the muscle-tendon passes. About 10 to 15 muscle fibers are attached to each Golgi tendon organ and this receptor is stimulated when these fibers are stretched. The Golgi tendon detects tension in contracting muscle and prevents excessive tension in muscles which can damage muscle fibers and tendons.

Sensory receptors

These are the receptors that sense different modalities of sensation. These include:

  • Mechanoreceptors detect touch, pressure, vibration, and tickle sensation. These include Ruffini’s endings, Pacinian corpuscles, Merkel’s discs, Miessner’s corpuscles, etc.
  • Thermoceptotrs detect warmth and cold.
  • Nociceptors produce the sensation of pain.
  • Electromagnetic receptors detect the visible spectrum of light.
  • Chemical receptors detect the concentration of different substances in body fluids such as taste buds, chemoreceptors in the hypothalamus, olfactory receptors, etc.

Read more about Sensory Receptors

Summary

Receptors are the biochemical structures that detect ligands or internal and external stimuli. They vary in their distribution, mechanism of action, and modality of sensation they detect. 

They may produce their response through several mechanisms such as altering gene transcription which is true for steroids and growth hormone receptors; opening ion channels directly which is true for GABA A and nicotinic receptors; stimulating secondary signal cascade which is true for most of the hormonal receptors such as TSH, LH, ACTH, etc; activating intrinsic tyrosine kinase activity which is true for insulin receptors; stimulating another tyrosine kinase in the cytosol which is true for erythropoietin, leptin, and interferon receptors, etc. 

Receptors are also classified based upon the type of stimulus they detect as hormonal receptors detect various hormones and activate secondary messenger cascade to produce a response; autonomic receptors are involved in sympathetic and parasympathetic transmission; immune receptors detect various bacterial products or necrotic bodies and produce an inflammatory response; muscle receptors provide feedback information to regulate muscles’ contractility; sensory receptors detect various sensory modalities such as pain, touch, pressure, pain, taste, smell, heat and cold, etc.

References

Miller EJ, Lappin SL. Physiology, Cellular Receptor. [Updated 2022 Sep 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554403/

Marzvanyan A, Alhawaj AF. Physiology, Sensory Receptors. [Updated 2022 Aug 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539861/

Hall, John E. 2015. Guyton and Hall Textbook of Medical Physiology. 13th ed. Guyton Physiology. London, England: W B Saunders

Membrane receptor illustration

Immune receptor illustration