Endocrine receptors

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Registrar: Dr. C Behrens

Consultant: Dr. T Mofokeng



  • About 100 years ago Starling coined the term “hormone” to describe secretin, a substance secreted by the small intestine into the bloodstream to stimulate pancreatic secretion.

  • Since the first connection between a viral oncogene, a mutated receptor tyrosine kinase and human cancer was made in 1984 (Ullrich, et al. 1984) it is well known that aberrant signalling by receptor tyrosine kinases is critically involved in human cancer and other hyper-proliferative diseases.

The multiple activities of the cells, tissues and organs of the body are coordinated by the interplay of several types of communication systems, including

  1. Neural: in which chemicals (neurotransmitters) are released at synaptic junctions and act locally to control cell function.

  2. Endocrine, in which lands or specialized cells release into the circulating blood chemicals (hormones) that influence the function of cells at another location in the body.

  3. Neuroendocrine, in which neurons secrete substances (Neuro hormones) that reach the circulating blood and influence the function of cells at another location in the body.

  4. Paracrine, in which cells secrete substances that diffuse into the extracellular fluid and affect neighbouring cells

  5. Autocrine, in which a cell secretes substances that affect the function of the same cell by binding to the cell surface receptors.

  6. Tropic hormones are secreted by the hypothalamus and pituitary gland and activate specific pathways for hormone synthesis and release. Typical examples are luteinizing hormone, and follicle-stimulating hormone, thyroid-stimulating hormone and adrenocorticotrophic hormone (LH, FSH, TSH, ACTH)

The major hormonal signalling programs are: (and all these are also used by paracrine factors)

  • G protein coupled receptors

  • Tyrosine kinase receptors

  • Serine/threonine kinase receptors

  • Ion channels

  • Cytokine receptors

  • Nuclear receptors

In contrast paracrine signalling are usually only used by paracrine factors and not by hormones.

Receptors on the Cell Surface:
Signalling pathways that begin with activation of receptors located on the surface of target cells. There are two essential functions that define hormone receptors:

  1. The ability to bind the hormone

  2. The ability to couple hormone binding to hormone action.

The cell-surface receptors can be classified according to the molecular mechanisms by which they accomplish their signalling function:

  • G protein-coupled receptors (e.g., receptors for adrenergic agents, muscarine cholinergic agents, glycoprotein hormones, glucagon and parathyroid hormone

  • Ligand-gated ion channels (e.g., nicotinic acetylcholine receptors)

  • Receptor tyrosine kinases (e.g., receptors insulin and insulin-like growth factor I [IGF-I])

  • Receptor serine/threonine kinases (e.g., atrial natriuretic factor receptor)

  • Cytokine receptors (e.g., receptors for growth hormone, prolactin and leptin)

Scatchard plot, describes the affinity of the hormone for the receptor. It is usually a straight line, but several mechanisms contribute to a non-linearity:

  • More than one type of receptor that binds to hormone

  • More than one binding site

  • Cooperative interactions among binding sites

Chemical structure and syntheses of hormones:

There are three general classes of hormones:

  1. Protein and polypeptides: including hormones secreted by the ant. and post. pituitary gland, the pancreas, the parathyroid gland, etc.

  2. The steroids secreted by the adrenal cortex (cortisol and aldosterone), the ovaries, the testes and the placenta.

  • The chemical structure of steroid hormones is similar to cholesterol, in most instances they are synthesized from cholesterol itself.

  • Large stores of cholesterol esters in cytoplasm vacuoles can be rapidly mobilized for steroid synthesis after a stimulus.

  • Once they are synthesized, they simply diffuse across the cell membrane and enter the interstitial fluid and then the blood.

  1. Derivatives of the amino acid tyrosine, secreted by the thyroid and the adrenal medullae.

  • The two groups of hormones derived from tyrosine are the thyroid hormones and adrenal medullary hormones.

Hormone formation:

Hormone formation may occur either in localized collection of specific cells, the endocrine glands or in cells that have additional roles. Many protein hormones, such as growth hormone, parathyroid hormone, prolactin, insulin and glucagon are produced in dedicated cells by standard protein synthetic mechanisms common to all cells. These secretory cells usually contain specialized secretory granules designed to store large amounts of hormone and to release the hormone in response to specific signals. Formation of small hormone molecules initiates with commonly found precursors, usually in specific glands such as the adrenals, gonads or thyroid.

  • Steroid hormone: The precursor is cholesterol, which is modified by various hydroxylation, methylations and demethylation to form glucocorticoid, androgens, estrogens and their biological derivatives.

  • In contrast the precursor of Vit D, 7-dehydrocholesterol, is produced in skin keratinocytes again from cholesterol, by a photochemical reaction.

  • Leptin, which regulate appetite and energy expenditure, is formed in adipocytes, thus providing a specific signal reflecting the nutritional state to the central nervous system.

  • Thyroid hormone synthesis occurs via a unique pathway. The thyroid cell synthesizes thyroglobulin, which is then iodinated at specific iodotyrosines. Certain of these couple to form the iodothyronine molecule within thyroglobulin, which is then stored in the lumen of the thyroid follicle. In order for this to occur, the thyroid cell must oxidize it via a specific peroxidase. Release of thyroxine (T4) from the thyroglobulin requires its phagocytosis and cathepsin-catalysed digestion by the same cells.

Endocrine diseases: Endocrine diseases fall into 4 broad categories:

  1. Hormone overproduction

  2. Hormone underproduction

  3. Altered tissue responses to hormones

Resistance to hormones can be causes by a variety of genetic disorders.


  • Growth hormone receptor in Laron dwarfism

  • Mutation in the Gsα gene in the hypoparathyroidism of pseudohypopararthyroidism type 1a.

  • Insulin resistance in muscle and liver central to the aetiology of type 2 diabetes mellitus.

  1. Tumours of the endocrine glands

Hormone Receptors and Their Activation:

Hormones must bind to specific receptors at the target cell. Receptors for some hormones are located on the target cell membrane, whereas other hormone receptors are located in the cytoplasm or the nucleus. When the hormone combines with its receptor, this usually initiates a cascade of reactions in the cell, with each stage becoming more powerfully activated so that even a small concentration of the hormone can have a large effect.

Each receptor is usually highly specific for a single hormone – this determines the type of hormone that will act on a particular tissue.
The location for the different types of hormone receptors is generally the following:

  • In or on the surface of the cell membrane.

    • Specific mostly for the protein peptide and catecholamine hormones

  • In the cell cytoplasm

    • Receptors for steroid hormones are found mostly in the cytoplasm

  • In the cell nucleus (nuclear receptor superfamily)

    • Receptors for the thyroid hormones are found in the nucleus

    • These hormones bind to intracellular receptors that function in the nucleus of the target cell to regulate gene expression. Classical hormones that utilize intracellular receptors include thyroid and steroid hormones.

    • In addition to above, lipophilic signalling molecules that utilize nuclear receptors include the following: (these are ligands for nuclear receptors)

      1. Derivatives of Vitamin A and D

      2. Endogenous metabolites such as oxysterols and bile acids

      3. Non-natural chemicals (xenobiotics)

The number of Hormone Receptors is Regulated

The receptor proteins themselves are often inactivated or destroyed during the course of their function, and at other times either they are reactivated or new ones are manufactured.

  • Down Regulation: binding of a hormone with its target cell receptors often causes the number of active receptors to decrease, either because of inactivation of some of the receptor molecules or because of decreased production of the receptors. This decreases the response of the target tissue to the hormone

  • Up Regulation: The stimulating hormone induces the formation of more receptor molecules than normal by the protein-manufacturing machinery of the target cell.

Intracellular Signalling after Hormone Receptor Activation:

Almost without exception, a hormone affects its target tissues by first forming a hormone-receptor complex. This alters the function of the receptor itself, and the activated receptor initiates the hormonal effects.

Some Hormones change membrane permeability:

Virtually al the neurotransmitter substances, such as acetylcholine and norepinephrine, combine with receptors in the postsynaptic membrane. This causes a change in the structure of the receptor, usually opening or closing a channel for one or more ions. It is the altered movement of these ions through the channels that causes the subsequent effects on the postsynaptic cells

Membrane associated receptor proteins usually consist of extracellular sequences that recognize and bind ligand, transmembrane anchoring hydrophobic sequences, and intracellular signalling is mediated by soluble second messengers or by activation of intracellular signalling molecules. Receptor dependent activation of heterotrimeric G-proteins, comprising α, β and γ.
Some hormones activate intracellular enzymes when they combine with their receptors:

Hormones activate an enzyme immediately inside the cell membrane when binding with the membrane receptor.

  • insulin binds with that portion of its membrane receptor that protrudes to the exterior of the cell that causes a structural change in the receptor molecule itself, causing the portion of the molecule that protrudes to the inside to become an activated kinase. The kinase then promotes phosphorylation of several different substances inside the cell.

  • Both the number of receptors expressed per cell, as well as their responses, is also regulated, thus providing a further level of control for hormone action.

  • Several mechanisms account for altered receptor function.

    • Receptor endocytosis causes internalization of cell-surface receptor

    • The hormone-receptor complex is subsequently dissociated, resulting in abrogation of the hormone signal.

    • Receptor trafficking may then result in recycling back to the cell-surface (e.g. insulin) or internalized receptor may undergo lysosomal degradation. Both these mechanisms may lead to impaired hormone signalling by down-regulation.

    • Receptor function may also be limited by action of specific phosphatases (e.g. SHP) or by intracellular negative regulation of the signalling cascade (e.g. SOCS proteins inhibiting JAK-STAT signalling)

    • Mutational changes in receptor structure can also determine hormone action. Constitutive receptor activation may be induced by activating mutations leading to endocrine organ hyper function, even in the absence of hormone.

Some hormones activate Genes by binding with intracellular receptors:

Several hormones, especially the steroid hormones and thyroid hormones, bind with the protein receptors inside the cell, not in the cell membrane. The activated hormone-receptor complex then binds with or activates specific portions of the DNA strands of the cell nucleus, which in turn initiates transcription of specific genes to form messenger RNA (mRNA). Newly formed proteins appear in the cell and become the controllers of new or increased cellular function.

Generally, the second messengers activate serine/threonine kinases, which phosphorylate serine or threonine residues, or both on proteins, whereas the receptor kinases are tyrosine-specific kinases that phosphorylate tyrosine residues. Examples of receptor tyrosine kinases are growth factor receptors such as those for insulin, insulin-like growth factor (IGF), epidermal growth factor and platelet –derived growth factor. Receptors in the cytokine receptor family, which include leptin, growth hormone and prolactin, activate associated tyrosine kinases in a variation on the theme.
Growth factor receptor tyrosine kinases activate transcription factors through cascades that involve both tyrosine phosphorylation and serine/threonine kinases such as mitogen-activated protein kinases, whereas the janus kinases (JAKs) activated by cytokine receptors directly tyrosine phosphorylate the signal transducer and activator of transcription (STAT) factors.

Receptor Tyrosine Kinases:

Receptor Tyrosine kinases have several structural mechanisms in common: an extracellular domain containing the ligand-binding site, a single transmembrane domain and an intracellular portion that includes the tyrosine kinase catalytic domain.
There are approximately 100 receptor tyrosine kinases, and can be classified into 16 subfamilies, based on the differences in the structure of the extracellular domain.
They mediate the biological action of a wide variety of ligands, including insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and vascular endothelial cell derived growth factor.
The insuline receptor closely resembles the type 1 receptor for IGFs. This is the receptor that mediates the biologic actions of IGF-I and therefore also plays an important role in the physiology of growth hormone (GH) in vivo. Although the kinase domains of receptors for insulin and IGF-I closely resemble other receptor tyrosine kinases, at least two distinctive features set them apart.

  1. The receptors are synthesized as proreceptors that undergo proteolytic cleavage into two subunits (β,α). The α subunit contains the ligand binding site and the β subunit includes the transmembrane and tyrosine kinase domains.

  2. Both receptors exist as α2β2 heterotetramers that are stabilized by intersubunit disulfide bonds. In contrast to other receptor tyrosine kinases, which are thought to dimerize in response ligand binding, the insulin receptor exists as a dimer of αβ monomers even in the absence of ligand.

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