Receptors: Classes, Roles and Characteristics

Introduction to Receptor and Definition

A receptor is a component of an organism, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signaling molecules may attach. A molecule which binds to a receptor is called a ligand, and may be a peptide or other small molecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin.
Receptors are macromolecules present both on the surface of, and within, the cell.

Major Roles of Receptors

These include:

1. Determines quantitative relationships between drug dose and pharmacological effect.
2. Determines drug action selectivity
3. Mediates antagonist (blocking) as well as agonist (activating) effects

Molecular Characteristics and Classification of Drug Receptors

Most receptors are proteins but nucleic acids (particularly DNA) are receptors for several drugs. Drug receptors can be classified into two different groups

1. Receptors for endogenous regulatory ligands such as hormones, growth factors, cytokines, autacoids, neurotransmitters etc. The function of these receptors is to sense the ligands in the environment and to initiate regulatory appropriate responses. These receptors function as signal transducers.
2. The usual macromolecules without endogenous ligand. The receptors for these drugs are enzymes, channels, transporters, structural proteins, nucleic acids etc. Examples include

• a. Dihydrofolate reductase enzymeas a ‘receptor’ for methotrexate used in the cancer treatment
• b. Calcium channels as a receptor for calcium channel blockers used in treatment of hypertension
• c. Colchicine used in the treatment of gouty arthritis, binds to and causes depolymerization of microtubules (structural proteins)
• d. Digoxin binds to and inhibit Na+ K+Atpase (a transporter) resulting in positive inotropic effect of the heart.
• e. Streptozotocin intercalates with DNA ( nucleic acids) resulting in the treatment of malignant tumor.

Classification of Receptors Based on Structure

The structures of receptors are very diverse and can broadly be classified into the following categories:

1. Type 1: L (ionotropic receptors): These receptors are typically the targets of fast neurotransmitters such as acetylcholine (nicotinic) and GABA. Activation of these receptors results in changes in ion movement across the membrane. are a group of transmembrane ion channel proteins which open to allow ions such as Na+, K+, Ca2+, or Cl- to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter. These receptors are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allostericbinding site).These receptors can be contrasted with metabotropic receptors(which use second messengers), voltage-gated ion channels(which open and close depending on membrane potential), and stretch-activated ion channels(which open and close depending on mechanical deformation of the cell membrane)
2. Type 3: kinase linked and related receptors: These receptors are composed of an extracellular domain containing the ligand binding site and an intracellular domain, often with enzymatic function, linked by a single transmembrane alpha helix. e.g. the insulin receptor. A kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP to specific target molecules (substrates); the process is termed phosphorylation. The opposite, an enzyme that removes phosphate groups from targets, is known as a phosphatase. Kinase enzymes that specifically phosphorylate tyrosine amino acids are termed tyrosine kinases.
3. Type 4: nuclear receptors: They are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors generally only happens when a ligand—a molecule that affects the receptor’s behavior —is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up-regulation or down-regulation of gene expression. A unique property of nuclear receptors that differentiates them from other classes of receptorsis their ability to directly interact with and control the expression of genomic DNA. As a consequence, nuclear receptors play key roles in both embryonic developmentand adult homeostasis. Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. Binding causes a conformational change in the receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression.
4. Type 2: G protein-coupled receptors (metabotropic): This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e.g. dopamine, metabotropic glutamate. They are composed of seven transmembrane alpha helices. They are called seven-transmembrane receptors because they pass through the cell membrane seven times. These receptors are coupled to different intracellular effector systems via G-proteins. There are two principal signal transduction pathways involving the G protein-coupled receptors (GPCR):

• a. the cAMP signal pathway and
• b. the phosphatidylinositol signal pathway. When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor(GEF). The GPCR can then activate an associated G-protein by exchanging its bound GDP for a GTP. The G-protein’s α subunit, ogether with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13)

References

1. RECEPTOR THEORY AND ITS ROLE IN DRUG THERAPY. Lippincott Nursing Center. Accessed August 8, 2021
2. The Pharmacology and Function of Receptors for Short-Chain Fatty Acids. Molecular Pharmacology. Accessed August 8, 20121
3. Functions of Receptor. Sino Biological. Accessed August 8, 2021
4. Receptor (biochemistry). Wikipedia. Accessed August 8, 2021