Cellular Receptors

– Summary:

A cellular receptor, is in molecular biology, a receptor associated with an intracellular signaling pathway, characterized by belonging to the family of receptors with intrinsic or associated enzymatic activity.

– Development:

They have an extracellular domain with multitude, intracellularly associated JAK kinases, and their signal transduction pathway involves the activation of STAT transcription factors, and MAPK-associated Ras pathway.

Thus, their activation by an external stimulus causes a cascade of internal enzymatic reactions that facilitate the adaptation of the cell to its environment, by means of second messengers.

Intracellular receptor

Intracellular receptors are components of the cell capable of identifying chemical messengers such as neurotransmitters and hormones.

They differ from extracellular receptors, which are found on the cell surface, because the ligands of these cannot pass through the lipid bilayer.

While intracellular receptor ligands can. Intracellular receptors are located in the cytosol and in the cell nucleus.

Both intracellular and extracellular receptors trigger a cascade of reactions that are involved in gene transcription.

The main difference between cytokines and interleukins is that cytokines are small proteins involved in cell signaling, whereas interleukins are a group of cytokines that regulate immune and inflammatory responses.

-Hormones

-Neurotransmitters

-Receptors as transcription factors

-Functions of cAMP Adenosine cyclic monophosphate

-Tyrosine kinase related receptors

-MAP kinases

-via JAK/STAT

-Phospholipids and Ca2+

-In the cytoskeleton

-Integrins

 Hormones

Hormones are chemical messengers secreted by the endocrine glands and discharged into the blood to travel to their target cells.

The mechanism of action of a hormone depends on its chemical nature. Most hormones trigger multiple effects on their target cells (i.e., short and long-term effects).

Hormones are classified into three types according to their composition: steroid, peptide and steroid-derived hormones.

Other hormones with different properties are vitamin D3, the thyroid hormone.

Its properties allow it to pass through the lipid membrane and consequently, these hormones have intracellular receptors, either in the cytosol or in the nucleus.

The complex formed, of hormone and receptor is directed to the nucleus, where it fixes to the DNA and stimulates the gene transcription.

Neither the hormone nor the receptor can, independently, react on the target cell.

Once a hormone has been released into the blood and has reached the vicinity of its target cells, it first fixes on specific receptors on those cells (or inside them).

The receptors for certain hormones such as peptides are found on the cell surface of the target cell.

Other receptors are located in the cytoplasm and fix only hormones that have diffused through the cell surface, examples of which are steroid hormones.

The binding of a hormone to its receptor communicates a message to the target cell, thus initiating signal transduction, i.e. the conversion of the initiating signal into a biochemical reaction.

The hormone-receptor complex appears to induce a protein kinase to phosphorylates certain regulatory proteins, thus generating a biological reaction to the hormone.

Peptide hormones, which are made up of peptides such as: insulin, glucagon, pituitary hormones (somatotrophin etc.), among others.

We also find the growth factors, the nerve growth factor (NGF) stimulates the development and maintenance of neurons, the epidermal growth factor EGF, stimulating the proliferation and differentiation of cells.

Another growth factor is platelet-derived growth factor (PDGF) which helps in the generation of fibroblasts and is essential for the synthesis of extracellular matrix and fibers.

Also tissue regeneration and coagulation in the case of platelets. We also find cytokines that help in the development and differentiation of blood cells.

A main characteristic of the growth factors is that they cannot pass the plasma membrane, so they need cell surface receptors, the best known of which are G-proteins.

Neurotransmitters

Neurotransmitters are released, when there is an arrival of an action potential and are released in the intersynaptic space.

There they bind to surface receptors, these can be ionic channels that depend on the ligand, which is the neurotransmitter

There are also other receptors, such as G-proteins, and these in turn stimulate ion channels thus allowing the flow of electrolytes.

Receptors as transcription factors

The transcription factors constitute a series of proteins that interact with regulatory groups of gene transcription, these will allow in the initiation of DNA transcription.

These transcription factors can be activated or deactivated by a set of proteins that constitute the cytoplasmic signalling and finally translated into a gene response.

Functions of cAMP Cyclic adenosine monophosphate

The cAMP can be used by protein kinase A (PKA) these have 4 regions, two regulatory and two catalytic, the cAMP binds to the regulatory region and allows the dissociation of the two catalytic regions.

Protein kinase A and protein phosphatase function as regulators of the activation and deactivation of other proteins.

Tyrosine kinase related receptors

There are receptor proteins such as tyrosine kinase that have catalytic activity, so that when a growth factor is bound they are dimerized and self-phosphorylated.

That is, they create binding sites for proteins with SH2 domain with which to interact with some proteins that are phosphorylated in tyrosine residues.

Thus their function is regulated by phosphorylation-dephosphorylation processes of these amino acids.

There are receptors that do not have kinase activity, so they need the help of non-receptor protein kinases but they also create binding sites for proteins with SH2 domains.

What happens is that when the growth factor arrives it induces the conformational change of the receptor protein, allowing the formation of a complex with non receptor protein kinases.

These kinases are associated and dimerise allowing autophosphorylation, with the subsequent creation of binding sites to proteins with SH2 domain.

Examples of this type of receptors are cytokine receptors, which are important in the immune response.

There are contrary enzymes that remove phosphate groups or dephosphorylate receptor proteins with tyrosine residues, these are called tyrosine phosphatases.

Other receptors, which have serine/threonine; such as the receptor for TGF, (interleukin 2 or Cell Growth Factor) these receptors activated by the action of the ligand, activate gene transcription factors such as SMADs.

In many different types of cancer, there is an alteration in the tyrosine kinase activity of the receptor, due to mutations, consequently, these molecules are used as very important therapeutic targets

MAP kinases

The stimulation of tyrosine kinase receptors generates self-phosphorylation, thus generating binding sites to SH2 proteins. This protein with this SH2 domain is called GRb2, with

a nucleotide exchange factor called SOS, as well as the entire complex of this protein when associated with the growth factor-activated receptor.

This causes SOS to associate with the plasma membrane and interact with Ras (a protein with similar activity to G-proteins).

Via JAK/STAT

The JAK/STAT signalling pathway involves three elements:

– Ligand receptor, most of which are cytokine receptors, hence the role of this pathway in the immune response.

– JAK receptor-associated proteins inside the cell

– STAT (Signal Transducer and Activator of Transcription) proteins, whose function is to act as transcription factors once activated by phosphorylation.

JAK proteins possess tyrosine kinase activity, i.e. they phosphorylate tyrosine residues.

These sites for SH2 allow the arrival and binding of STAT proteins to the phosphotyrosine residues of the receptor, when this occurs the JAK proteins reactivate their tyrosine-kinase function and phosphorylate STAT.

As a consequence, STAT proteins dissociate from the receptor and bind to form a dimer (dimerization) which then moves to the cell nucleus where it binds to DNA and acts to promote gene transcription.

The ligands of the JAK/STAT pathway in most cases belong to the cytokine family, these include Interferon or Interleukin molecules.

Another type of ligand that acts through this signaling pathway is growth factors.

The importance of the JAK/STAT signalling pathway lies in its close relationship with immune system mechanisms such as inflammation.

It has been seen that inhibitors of JAK proteins can have a positive effect on some autoimmune diseases such as rheumatoid arthritis.

Phospholipids and Ca2+

Another cellular signaling pathway is the second messenger pathway, such as those derived from membrane phospholipids, one of the best known of which is PIP2 (phosphatidyl inositol bisphosphate), a component of the plasma membrane and located on the inner side of the membrane.

The intracellular signaling pathway derived from second messengers begins when a protein  G activates phospholipase C (PLC).

Activated its PLC-B isoform by a G protein and another PLC-Y has SH2 domains and therefore is associated with tyrosine kinase proteins IP3(inositol triphosphate).

It acts through ionic channels of the calcium reservoir such as the endoplasmic reticulum (ER) which releases Ca2+, the Ca2+ is regulated by calmodulin, building a complex between the two.

Calmodulin/Ca2+ are important because they are needed to activate CaM quinanas. These regulate the release of neurotransmitters.

This intracellular second message signaling pathway is very important in many neurological, immune and endocrine processes.

In the cytoskeleton

In the cytoskeleton receptors such as RHo activate the protein serine/threonine kinase called Rho kinase, these increase the phosphorylation of the light chain myosin II thus causing the actin and myosin filaments to assemble.

Integrins

Like the members of the cytokine receptor superfamily, integrins have short cytoplasmic segments that have no enzymatic activity and so are associated with a protein kinase called AF

The binding of integrins to the extracellular matrix stimulates the activity of FAK leading to its self-phosphorylation, which leads to the activation of RAS and MAP cascade kinases.

Embryological signalling

Notch is a large protein with a transmembrane domain that acts as a receptor with transmembrane proteins from adjacent cells.

This union creates proteolytic rupture of notch releasing an intracellular domain of notch that is translocated to the nucleus and acts with the transcription factor CBF 1 from here the gene transcription occurs.

Important functions of this cell signaling pathway are fulfilled in embryonic development.

It participates in the determination of cell types, the development of extremities, nervous system, skeleton, lungs, hair, teeth, and gonads.

The G-proteins

Guanine nucleotide binding protein, are a family of proteins that transduce signals from the receptor to which they are coupled.

Their name derives from the initial G of guanosine, they act as biological switches through signal transduction

In this way, a stimulus from outside the cell, which may be a ligand, enters the cell and accesses the receptor associated with G-protein or GPCR.

This triggers a cascade of enzymatic activities or second messengers in response.

Up to one or more effector proteins and depend on the nucleotide guanosine triphosphate (GTP) for activation.

G-protein-coupled receptors (GPCRs) comprise the targets of several biogenic amines.

Eicosanoids and other molecules that send signals to target cells such as lipids, hormonal peptides, opiates, amino acids (GABA), and many other protein peptides and ligands.

Effectors that are regulated by G-protein include enzymes such as adenyl cyclase, phospholipase C, phosphodiesterases and plasma membrane ion channels selective for Ca²+ and K+.

Because of their number and physiological importance, GPCRs are widely used targets for drugs, perhaps half of all non-antibiotic drugs are directed to these receptors.

They constitute the third largest family of genes in humans.

G-protein-associated receptors are recognized by their serpentine structure, that is, with seven transmembrane domains.

They comprise a multitude of proteins, since the term corresponds to a family of transmembrane receptors.

They detect extracellular signals and transmit them to signal transduction cascades inside the cell.

This in turn triggers relevant responses, for example, modulation of gene transcription.

They recognize a variety of ligands, such as neurotransmitters, pheromones, hormones, and a variety of peptides and proteins.

Their dysfunction causes disease, and they are used as targets in chemotherapy.

– Conclusions:

The term «receptor» refers to the proteins or glycoproteins that allow the interaction of certain substances with the mechanisms of cellular metabolism.

They are present in the plasma membrane, in the cytosol organelle membrane or in the cell nucleus.

They are joined by other chemicals called signaling substances, such as hormones, neurotransmitters or other ligands, such as interferons, interleukins, other cytokines, erythropoietin, and growth hormone

-Keywords: cellular receptors, membrane receptors, cytosol receptors, nuclear receptors, JAK kinases, STAT transcription, Ras pathway, MAP kinases, cytokine receptors, G proteins, tyrosine kinase, Rho receptor.

References:

– Review of different sources, 04/2020