Let us make an in-depth study of the hormone receptors. After reading this article you will learn about 1. Meaning of Hormone Receptors and 2. Types of Hormone Receptors.
Meaning of Hormone Receptors:
A hormone receptor is a receptor protein on the surface of a cell or in its interior that binds to a specific hormone. The hormone causes many changes that take place in the cell. Binding of hormones to hormone receptors often trigger the start of a biophysical signal that can lead to further signal transduction pathways, or trigger the activation or inhibition of genes.
Types of Hormone Receptors:
Peptide Hormone Receptors:
Are often trans membrane proteins. They are also called G-protein- coupled receptors, sensory receptors or ionotropic receptors. These receptors generally function via intracellular second messengers, including cyclic AMP (cAMP), inositol 1, 4, 5-triphosphate (IP3) and the calcium (Ca2+)—calmodulin system.
Steroid Hormone Receptors and Related Receptors:
Are generally soluble proteins that function through gene activation. Their response elements are DNA sequences (promoters) that are bound by the complex of the steroid bound to its receptor. The receptors themselves are zinc-finger proteins. These receptors include those for glucocorticoids, estrogens, androgens, thyroid hormone (T3), calcitriol (the active form of vitamin D), and the retinoids (vitamin A).
Receptors for Peptide Hormones:
With the exception of the thyroid hormone receptor, the receptors for amino acid derived and peptide hormones are located in the plasma membrane. Receptor structure is varied.
Some receptors consist of a single polypeptide chain with a domain on either side of the membrane, connected by a membrane-spanning domain. Some receptors are comprised of a single polypeptide chain that is passed back and forth in serpentine fashion across the membrane, giving multiple intracellular, trans membrane, and extracellular domains. Other receptors are composed of multiple polypeptides. Ex. The insulin receptor is a disulfide linked tetramer with the β-subunits spanning the membrane and the α-subunits located on the exterior surface.
Subsequent to hormone binding, a signal is transduced to the interior of the cell, where second messengers and phosphorylated proteins generate appropriate metabolic responses. The main second messengers are cAMP, Ca2+, inositol triphosphate (IP3), and diacylglycerol (DAG).
Proteins are phosphorylated on serine and threonine by cAMP-dependent protein kinase (PKA) and DAG-activated protein kinase C (PKC). Additionally a series of membrane-associated and intracellular tyrosine kinases phosphorylate specific tyrosine residues on target enzymes and other regulatory proteins.
The hormone-binding signal of most, but not all, plasma membrane receptors is transduced to the interior of cells by the binding of receptor-ligand complexes to a series of membrane-localized GDP/GTP binding proteins known as G-proteins. The classic interactions between receptors, G-protein transducer, and membrane-localized adenylate cyclase are illustrated using the pancreatic hormone glucagon as an example.
When G-proteins bind to receptors, GTP exchanges with GDP bound to the α-subunit of the G-protein. The Ga-GTP complex binds adenylate cyclase, activating the enzyme. The activation of adenylate cyclase leads to cAMP production in the cytosol and to the activation of PKA, followed by regulatory phosphorylation of numerous enzymes. Stimulatory G-proteins are designated Gs, inhibitory G-proteins are designated Gi.
A second class of peptide hormones induces the transduction of 2 second messengers, DAG and IP3. Hormone binding is followed by interaction with a stimulatory G-protein which is followed in turn by G-protein activation of membrane-localized phospholipase C-y, (PLC-y). PLC-y hydrolyzes phosphatidylinositol bisphosphate to produce 2 messengers viz. IP3, which is soluble in the cytosol, and DAG, which remains in the membrane phase.
Cytosolic IP3 binds to sites on the endoplasmic reticulum, opening Ca2+ channels and allowing stored Ca2+ to flood the cytosol. There it activates numerous enzymes, many by activating their calmodulin or calmodulin-like subunits.
DAG has 2 roles-it binds and activates PKC, and it opens Ca2+ channels in the plasma membrane, reinforcing the effect of IP3. Like PKA, PKC phosphorylates serine and threonine residues of many proteins, thus modulating their catalytic activity.
Insulin Receptor:
Is a trans membrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors. Two alpha subunits and two beta subunits make up the insulin receptor. The beta subunits pass through the cellular membrane and are linked by disulfide bonds. The alpha and beta subunits are encoded by a single gene (INSR). The insulin receptor has been designated as CD220 (cluster of differentiation 220).
Function of insulin receptor-effect of insulin on glucose uptake and metabolism:
Insulin binds to its receptor which in turn starts many protein activation cascades.
These include—
i. Translocation of Glut-4 transporter to the plasma membrane and influx of glucose
ii. Glycogen synthesis
iii. Glycolysis and fatty acid synthesis
Insulin receptors (a family of tyrosine kinase receptors), mediate their activity by causing the addition of a phosphate group to particular tyrosine’s on certain proteins within a cell. The ‘substrate’ proteins which are phosphorylated by the insulin receptor include a protein called ‘IRS-1’ for ‘Insulin Receptor Substrate-1’.
IRS-1 binding and phosphorylation eventually leads to an increase in the high affinity glucose transporter (Glut4) molecules on the outer membrane of insulin-responsive tissues, including muscle cells and adipose tissue, and therefore to an increase in the uptake of glucose from blood into these tissues. Briefly, the glucose transporter (Glut4) is transported from cellular vesicles to the cell surface, where it then can mediate the transport of glucose into the cell. Glycogen synthesis is also stimulated by the insulin receptor via IRS-1.
Pathology of insulin receptors:
The main activity of activation of the insulin receptor is inducing glucose uptake. For this reason ‘insulin insensitivity’, or a decrease in insulin receptor signaling, leads to diabetes mellitus type 2 – the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose), and all the sequelae which result from diabetes. Patients with insulin resistance may display acanthosis nigricans.
A few patients with homozygous mutations in the INSR gene have been described, which causes Donohue syndrome or Leprechauns. This autosomal recessive disorder results in a totally non-functional insulin receptor. These patients have low set, often protruberant ears, flared nostrils, thickened lips, and severe growth retardation.
In most cases, the outlook for these patients is extremely poor with death occurring within the first year of life. Other mutations of the same gene cause the less severe Rabson-Mendenhall syndrome, in which patients have characteristically abnormal teeth, hypertrophic gingiva (gums) and enlargement of the pineal gland. Both diseases present with fluctuations of the glucose level—after a meal the glucose is initially very high, and then falls rapidly to abnormally low levels.
Degradation of insulin and its receptors:
Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule is finally degraded about 71 minutes after its initial release into circulation.
Glucagon Receptor:
It is a 62 kDa peptide that is activated by glucagon and is a member of the G- protein coupled family of receptors, coupled to Gs. Stimulation of the receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP. Glucagon receptors are mainly expressed in liver and in kidney with lesser amounts found in heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex, and G.I. tract.
Steroid Hormone Receptors:
Are proteins that have a binding site for a particular steroid molecule. Their response elements are DNA sequences that are bound by the complex of the steroid bound to its receptor. The response element is part of the promoter of a gene. Binding by the receptor activates or represses, as the case may be, the gene controlled by that promoter. It is through this mechanism that steroid hormones turn genes on (or off).
The DNA sequence of the glucocorticoid (a protein homodimer) response element is:
5′-AGAACAnnnTGTTCT-3′
3′ TCTT GTnnnACAAGA-5′
where n represents any nucleotide (a palindromic sequence)
The glucocorticoid receptor, like all steroid hormone receptors, is a zinc-finger transcription factor; there are four zinc atoms each attached to four cysteine’s.
For a steroid hormone to turn gene transcription on, its receptor must:
(i) Bind to the hormone
(ii) Bind to a second copy of itself to form a homodimer
(iii) Be in the nucleus, moving from the cytosol if necessary
(iv) Bind to its response element
(v) Activate other transcription factors to start transcription
Each of these functions depends upon a particular region of the protein (Ex. The zinc fingers for binding DNA). Mutations in any one region may upset the function of that region without necessarily interfering with other functions of the receptor.
Nuclear Receptor Superfamily:
The zinc-finger proteins that serve as receptors for glucocorticoids and progesterone are members of a large family of similar proteins that serve as receptors for a variety of small, hydrophobic molecules. These include other steroid hormones like the mineralocorticoid-aldoster- one, estrogens, the thyroid hormone (T3), calcitriol (the active form of vitamin D), rednoids—vitamin A (retinol) and its relatives-retinal/retinoic acid, bile acids and fatty acids.
These bind members of the superfamily called Peroxisome Proliferator Activated Receptors (PPARs). They got their name from their initial discovery as the receptors for drugs that increase the number and size of peroxisomes in cells.
In every case, the receptors consists of at least three functional modules or domains from N-terminal to C-terminal, these are:
i. A domain needed for the receptor to activate the promoters of the genes being controlled
ii. The zinc-finger domain needed for DNA binding (to the response element)
iii. The domain responsible for binding the particular hormone as well as the second unit of the dimer
Receptors for Thyroid Hormones:
Are members of a large family of nuclear receptors that include those of the steroid hormones. They function as hormone-activated transcription factors and thereby act by modulating gene expression.
Thyroid hormone receptors bind DNA in absence of hormone:
Usually leading to transcriptional repression. Hormone binding is associated with a conformational change in the receptor that causes it to function as a transcriptional activator.
Mammalian thyroid hormone receptors are encoded by two genes, designated alpha and beta. Further, the primary transcript for each gene can be alternatively spliced, generating different alpha and beta receptor isoforms. Currently, four different thyroid hormone receptors are recognized as-(i) α-1 (ii) α-2 (iii) β-1 and (iv) β-2.
Like other members of the nuclear receptor superfamily, thyroid hormone receptors encapsulate three functional domains:
i. A transactivation domain at the amino terminus that interacts with other transcription factors to form complexes that repress or activate transcription. There is considerable divergence in sequence of the transactivation domains of alpha and beta isoforms and between the two beta isoforms of the receptor.
ii. A DNA-binding domain that binds to sequences of promoter DNA known as hormone response elements.
iii. A ligand-binding and dimerization domain at the carboxy-terminus.
Disorders of thyroid hormone receptors:
A number of humans with a syndrome of thyroid hormone resistance have been identified, and found to have mutations in the receptor beta gene which abolish ligand binding. Clinically, such individuals show a type of hypothyroidism characterized by goiter, elevated serum concentrations of T3 and thyroxine and normal or elevated serum concentrations of TSH.
More than half of affected children show attention-deficit disorder, which is intriguing considering the role of thyroid hormones in brain development. In most affected families, this disorder is transmitted as a dominant trait, which suggests that the mutant receptors act in a dominant negative manner.
Adrenergic Receptors (or Adrenoceptors):
Are a class of G-protein coupled receptors that are targets of the catecholamine’s. Adrenergic receptors specifically bind their endogenous ligands, the catecholamine’s adrenaline and noradrenalin (called epinephrine and norepinephrine), and are activated by these.
Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic response (i.e. the fight-or-flight response) viz. the heart rate will increase and the pupils will dilate, energy will be mobilized, and blood flow diverted from other, non-essential, organs to skeletal muscle. There are several types of adrenergic receptors, but there are two main groups viz. a-adrenergic and P-adrenergic.
α-Adrenergic receptors:
These receptors bind noradrenalin (norepinephrine) and adrenaline (epinephrine). Phenylephrine is a selective agonist of the a-receptor. They exist as α1-adrenergic receptors and α2-adrenergic receptors.
β-Adrenergic receptors:
These receptors are linked to Gs proteins, which in turn are linked to adenyl cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP. Downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), which mediates some of the intracellular events following hormone binding.
Role in circulation:
Epinephrine reacts with both α and β-adrenoreceptors, causing vasoconstricdon and vasodilation, respectively. Although receptors are less sensitive to epinephrine, when activated, they override the vasodilation mediated by β-adrenoreceptors. The result is that high levels of circulating epinephrine cause vasoconstriction. Lower levels of epinephrine dominates β-adrenoreceptor stimulation, producing an overall vasodilation.
The mechanism of adrenergic receptors:
Adrenaline or noradrenalin is receptor ligands to either α1, α2 or β-adrenergic receptors, a, couples to Gq, which results in increased intracellular Ca2+ which results in smooth muscle contraction. α2 on the other hand, couples to Gi, which causes a decrease of cAMP activity, resulting in smooth muscle contraction. β receptors couple to Gs, and increase intracellular cAMP activity, resulting in heart muscle contraction, smooth muscle relaxation and glycogenolysis.
Functions of α-receptors:
α-Receptors have several functions in common. They are:
(i) Vasoconstriction of arteries to heart (coronary artery)
(ii) Vasoconstriction of veins
(iii) Decrease motility of smooth muscle in gastrointestinal tract
Alpha-1 adrenergic receptor:
Alpha-1 -adrenergic receptors are members of the G protein-coupled receptor superfamily. Upon activation, a heterotrimeric G-protein, Gq, activates phospholipase C (PLC), which causes an increase in IP3 and calcium. This triggers all other effects. Specific actions of the β1 receptor mainly involve smooth muscle contraction.
It causes vasoconstriction in many blood vessels including those of the skin & gastrointestinal system and to kidney (renal artery) and brain. Other areas of smooth muscle contraction are for instance – ureter, vas deferens, hairs (arrector pili muscles), uterus (when pregnant), urethral sphincter, bronchioles (although minor to the relaxing effect of β2 receptor on bronchioles). Further effects include glycogenolysis and gluconeogenesis from adipose tissue and liver, as well as secretion from sweat glands and Na reabsorption from kidney.
Alpha-2 adrenergic receptor:
There are 3 highly homologous subtypes of α2 receptors viz. α2A, α2B, and α2C. Specific actions of the a2-receptor include:
i. Inhibition of insulin release in pancreas
ii. Induction of glucagon release from pancreas
iii. Contraction of sphincters of the gastrointestinal tract
Beta-1 adrenergic receptor:
Specific actions of the β1 receptor include:
i. Increase cardiac output, both by raising heart rate and increasing the volume expelled with each beat (increased ejection fraction)
ii. Renin release from juxtaglomerular cells
iii. Lipolysis in adipose tissue
Beta-2 adrenergic receptor:
Specific actions of the β2 receptor include:
i. Smooth muscle relaxation, e.g. in bronchi
ii. Relaxes urinary sphincter and pregnant uterus
iii. Relaxes detrusor urinary muscle of bladder wall
iv. Dilates arteries to skeletal muscle
v. Glycogenolysis and gluconeogenesis
vi. Contract sphincters of GI tract
vii. Thickened secretions from salivary glands
viii. Inhibit histamine-release from mast cells
ix. Increase renin secretion from kidney