Table of Contents
Signal Transduction – Communication Between Cells and their Surroundings
Both extracellular and intracellular messengers are needed for the transmission of information. The classical definition of hormone is any member of a class of signaling molecules produced by glands in multicellular organisms that are transported by the circulatory system to target distant organs to regulate physiology and behavior. The term hormone is sometimes extended to include chemicals produced by cells that affect the same or neighboring cells.
To do that, hormones use the following mechanisms: endocrine (transportation of information to an organ via the bloodstream), autocrine (produced by signaling cells that can also bind to the ligand that is released, which means the signaling cell and the target cell can be the same or occur by transferring signaling molecules across gap junctions), or paracrine (involving being directed at neighboring cells). Paracrine signaling is produced and liberated by specialized local cells where the signals elicit quick responses and last only a short amount of time. Gut hormones are frequently paracrine.
In contrast to this, the body can produce mediators in unspecialized cells and use them for communication. Examples of this are prostaglandins. Additionally, there are transmitters, which are used in the nervous system.
The transition between these 3 groups is fluent. The correct transduction of the signal into the cell with the aid of receptors is crucial for successful communication.
Receptor types and their signal cascades
The most important biochemical receptor classes and the intracellular signaling pathways are outlined below. Four types of receptor classes are distinguished:
1. G protein-coupled receptors
These form the largest group of receptor classes. The receptor (G-protein coupled receptor or GPCR) consists of 7 transmembrane domains and it is coupled with an inactive heterotrimeric G protein. This protein consists of 3 subunits (SU): an α-SU, a β-SU, and a γ-SU. The α-SU binds GDP. β-SU and a γ-SU work together.
When a ligand binds to the GPCR it causes a conformational change in the GPCR. The GPCR can then activate the associated G protein by exchanging its bound guanosine-5′-diphosphate (GDP) for guanosine-5′-triphosphate (GTP). As a consequence, the G protein’s α subunit, together with the bound GTP, can then dissociate from the β/γ subunits to further affect intracellular signaling proteins or target functional proteins. Both complexes interact with effector proteins within the cell. With the intrinsic GTPase activity of the α-SU, GTP is hydrolyzed to GDP and the 3 SUs return to their original state.
Two of the most frequent signaling pathways occur via the following:
Adenylate cyclase: This effector protein is either stimulated by Gs proteins or inhibited by Gi-proteins (stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi)). It catalyzes the formation of adenosine 3′,5′-cyclic monophosphate (cAMP) from adenosine triphosphate (ATP). As a 2nd messenger, cAMP has several points of application within the cell.
IP3: The effector protein phospholipase C splits PIP2 (phosphatidylinositol-4,5-bisphosphate) into IP3 (Inositol-1,4,5-triphosphate) and DAG (diacylglycerol). IP3 increases the calcium level in the cell via other receptors, and DAG activates protein kinase C.
2. Receptors with intrinsic kinase activity
These receptors consist of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular kinase domain. This class is roughly divided into 2 versions:
Tyrosine kinases: The kinase phosphorylates tyrosine residues of the receptor. These are then recognized by other signal domains and the signal is transported in the cell via several pathways. The important pathways are the mitogen-activated protein (MAP)-kinase-pathway, a cascade of different kinases, phospholipase Cγ, and PI3 lipase.
Serine-threonine kinases: The kinase phosphorylates serine/threonine residues of side chains of other signal proteins – not the receptor proteins. The information is transduced via the Smad signaling pathway, members of the transforming growth factor (TGF)-β superfamily.
3. Receptors with associated kinases
The receptors do not possess any intrinsic kinase activity, but they bind kinases directly or via adapting proteins. These kinases are activated if a ligand binds. An example of such an associated kinase is the Janus kinase involving the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway. The JAK-STAT signaling pathway transmits information from extracellular chemical signals to the nucleus resulting in deoxyribonucleic acid (DNA) transcription and expression of genes involved in immunity, proliferation, differentiation, apoptosis, and oncogenesis. Disrupted or dysregulated JAK-STAT functionality can result in immune deficiency syndromes and cancers.
4. Nuclear receptors
Nuclear receptors are located within the cell and are thus only available for lipophilic ligands, which are able to diffuse through the membrane. All of them act as ligand-activated transcription factors. Steroid receptors are located in the cytoplasm. If a ligand binds, they migrate into the nucleus and act on the DNA as enhancers.
Receptors for D-vitamins or thyroid hormones, e.g., bind to the DNA in an inactive form as repressors if the ligand does not bind. Ligand binding results in a change in conformation, which in turn leads to gene expression. Binding of the thyroid hormone results in a conformational change in its nuclear receptor TR which displaces corepressor from the receptor/DNA complex and recruits coactivator proteins. The DNA/TR/coactivator complex then recruits ribonucleic acid (RNA) polymerase that transcribes downstream DNA into messenger RNA and eventually protein formation that results in a change in cell function.
Hormones – The Body’s Messengers
Insulin and glucagon – blood sugar level
Synthesis of insulin and glucagon
Insulin is synthesized in the B cells of the endocrine pancreas. Glucagon is produced in the A cells. Insulin consists of an A-chain (21 amino acids), and a B-chain (30 amino acids), which are connected to each other by disulfide bridges. Glucagon is a peptide consisting of 28 amino acids.
Stimuli for the secretion of insulin and glucagon
Insulin secretion is triggered by an increase in blood glucose level and by amino acids, free fatty acids, gastrointestinal peptides, and parasympathetic activity. As the antagonist, glucagon is secreted during hypoglycemia or during stimulation with catecholamines or amino acids.
Insulin and glucagon receptors
The insulin molecule binds to a tetrameric membrane protein, which consists of 2 tyrosine kinase receptors. Glucagon causes an increase in intracellular cAMP via a G protein-coupled receptor and adenylate cyclase.
Effects of insulin and glucagon
Insulin increases resorption of glucose into the body cells, from the blood by activating the glucose receptor. The liver and pancreas glucose transporter is called GLUT 2 and the muscle and fat glucose transporter is called GLUT 4. It also promotes the intake of amino and fatty acids and increases glycogen synthesis in the liver. Glucagon antagonistically promotes the degradation of liver glycogen, thereby rapidly increasing blood sugar level when it is too low.
Adrenaline and noradrenaline
Catecholamines are used within the body both as transmitters and as hormones. Here we discuss their function as hormones.
Synthesis of adrenaline and noradrenaline
Both hormones are synthesized in the adrenal medulla from tyrosine, resulting in 80% adrenaline and 20% noradrenaline. In the blood, however, the ratio is 1:5 since noradrenaline is liberated at many sympathetic nerve endings and escapes the synaptic cleft.
Stimuli to the secretion of adrenaline and noradrenaline
Synthesis is stimulated by both the sympathetic nervous system and glucocorticoids.
Adrenaline and noradrenaline receptor
Both hormones bind to G-protein-coupled receptors. The following are identified: α1- and α2-adrenoreceptors, and β1-, β2-, and β3-adrenoreceptors. Noradrenaline has a preference for α-adrenoreceptors; adrenaline binds better to β-adrenoreceptors. The 2 differ in their coupled G-proteins and thus differ in their signaling pathways. Note that Gq proteins are a class of G proteins that work to activate phospholipase C (PLC), participating in a variety of cellular signaling pathways. The letter ‘q’ does not stand for any particular function.
Overview of adrenoreceptors
|α1||Gq||Phospholipase Cβ ↑||DAG and IP3 ⇒ Ca++ ↑||Contraction of musculature; stimulation of glycogenolysis|
|α2||Gi||Adenylate cyclase ↓||cAMP ↓||Inhibits lipolysis and insulin liberation|
|β1||Gs||Protein kinase A ↑||cAMP ↑||Heart rate ↑, impulse conduction velocity ↑, and contractility ↑|
|β2||Relaxation of smooth muscles, glycogenolysis ↑, and lipolysis ↑|
|β3||Lipolysis in brown fat tissue ↑|
Effects of adrenaline and noradrenaline
With respect to metabolism, catecholamines are designed to make stored energy available for use. This means that they promote glycogenolysis and lipolysis and that, among other activities, they inhibit insulin secretion and storage of glucose.
With respect to the heart, they have a positive effect on cardiac output, and in the vascular system, they cause both vasoconstriction and vasodilation – depending on whether α1-adrenoreceptors or β2-adrenoreceptors are expressed.
Renin-angiotensin-aldosterone (RAAS) system
The RAAS connects kidney function with blood pressure and is an important part of blood pressure regulation.
Synthesis of the renin-angiotensin-aldosterone system
The different components of the system are formed at different locations within the body:
- Renin: Synthesized in the epithelioid cells of the juxtaglomerular apparatus in the kidney, near the macula densa. The active enzyme is liberated via exocytosis.
- Angiotensinogen: Produced in the liver and in fat tissue
- Angiotensin-I-converting-enzyme (ACE): Synthesized in the endothelium, mainly in the lung
- Aldosterone: Produced in the zona glomerulosa of the adrenal cortex
Effects of the RAAS
When the blood pressure decreases in the efferent arteriole of the glomerulus or sodium is low in the macula densa, renin is liberated. It splits angiotensinogen into angiotensin 1. This is converted into angiotensin 2 by ACE. Angiotensin 2 has several effects:
- Stimulation of sodium reabsorption in the proximal tubule
- Stimulation of aldosterone secretion: Aldosterone increases sodium resorption in the collecting ducts and the connecting tubules
- Central stimulation of the sensation of thirst and a desire for salt resulting in increased intake of water and salt
- Stimulation of antidiuretic hormone (ADH) secretion resulting in increased water retention
- Contraction of vascular smooth muscle cells
Blood volume and consequently blood pressure are increased via the 1st 4 mechanisms.
Angiotensin acts via several angiotensin receptors, which signal by means of both phospholipase C and inhibition of adenylate cyclase. There are different isoforms. One of them inhibits renin liberation in an autoregulative manner.
Hypothalamic-pituitary-adrenal (HPA) axis
This axis plays a central role in the hormone system of the body. As the name suggests, it consists of the hypothalamus, the hypophysis (the pituitary gland), the adrenal gland, and other target organs.
The hypothalamus produces releasing hormones that lead to a release of the respective hormones in the pituitary gland and also inhibiting hormones, which inhibit the release of certain hormones.
The pituitary gland consists of the posterior lobe/neurohypophysis and the anterior lobe/adenohypophysis.
The neurohypophysis is the location for the storage and release of ADH and oxytocin.
Attention: The hormones of the posterior hypophysis are synthesized in the hypothalamus. They are then taken to the neurohypophysis via axonal transport.
The adenohypophysis synthesizes and secretes 6 hormones under regulation by hypothalamic releasing hormones. Their release is solely triggered by the hormones of the hypothalamus. Four of the 6 hormones are glandotropic, i.e. they have an effect on other glands. Individual hormones are given their own specific sections below.
The system is kept within its limits via negative feedback to the hypothalamus by the hormones released in target organs. Thus, pathologically absent feedback can lead to defective regulation.
|Hypothalamus||Pituitary Gland||Target Organ|
|TRH (thyrotropin-releasing hormone)||Thyroid-stimulating hormone (TSH)||Thyroid gland|
|CRH (corticotropin-releasing hormone)||Corticotropin (ACTH), melanotropin (MSH, forms from pro-opiomelanocortin (POMC) during ACTH-synthesis)||Adrenal gland: mineralocorticoids, glucocorticoids, and sex hormones. Skin: melanin production|
|GnRH (gonadotropin-releasing hormone)||Follicle-stimulating hormone (FSH), luteinizing hormone (LH)||Ovary and testicle: sex hormones, ovulation, and spermatogenesis|
|PRH (prolactin-releasing hormone)||Prolactin (PRL)||Mammary glands lactation|
|GHRH (growth-hormone-releasing hormone)||Somatotropin (STH, growth-hormone = GH)||Liver: insulin-like growth factor-1 (IGF-1)|
ADH and oxytocin – hormones of the neurohypophysis
ADH acts on the collecting ducts of the kidney. It binds to vasopressin 2 (V2)-receptors and causes the integration of aquaporin 2 into the apical membrane of the cells. The consequence is increased water retention, thus compensating the stimulus for ADH-release, which is the hyperosmolarity of the blood.
Oxytocin, the hormone for lactation, is liberated during mechanical stimulation of the nipple when an infant sucks. It causes constriction of the myoepithelium of the mammary glands. This aids the infant when drinking.
Growth hormone (GH)
The growth hormone (GH), or somatotropin, influences body growth and metabolism.
GH – location of synthesis and stimuli
GH is produced and secreted in the adenohypophysis. The release is mainly triggered by the GH-releasing hormone of the hypothalamus. Other stimuli are ghrelin, thyroid hormones, steroid hormones, amino acids, low glucose level, physical activity, and deep sleep.
GH binds to receptors associated with tyrosine kinase. Especially in the liver, insulin-like growth factors (IGF) are induced and released into the blood plasma, thus initiating growth-enhancing effects. Furthermore, IFs are produced in the growth plate, which promotes bone growth in a paracrine fashion. IFs act on the target cells via tyrosine kinase receptors.
Effect of the growth hormone
Postnatal growth is promoted by GH/IF. These also mediate several metabolic effects, such as the promotion of bone growth, the growth of organs, and growth in muscle mass. In the adult organism, the system contributes to tissue homeostasis and regeneration processes.
With respect to metabolism, GH reinforces protein biosynthesis, promotes the release of glucose, and inhibits its utilization. It also promotes lipolysis and the degradation of fatty acids.
Synthesis of glucocorticoids
Glucocorticoids originate from the zona fasciculata (the middle zone) of the adrenal medulla and are steroid hormones, i.e.: they diffuse through membranes and directly act within the cell.
Stimuli for the secretion of glucocorticoids
The release of glucocorticoids is a part of the HPA axis. In the hypothalamus, the CRH is liberated: in turn, it causes the release of ACTH, which causes the secretion of cortisol, the main representative of the glucocorticoids.
Cortisol binds to 2 receptors in the cytosol. The type 1 receptor has a high affinity to cortisol but also binds aldosterone. However, the intracellular concentration of cortisol is usually greater so that the receptor binds almost exclusively to cortisol. The type 2 receptor specifically binds to cortisol, but with a lower affinity. At high concentrations, the receptor plays a particular role in stress situations.
Effects of glucocorticoids
Cortisol is a stress hormone, and most of its functions can be deduced from this designation. It promotes gluconeogenesis, it increases the fatty acid level in the blood and it decreases anabolic metabolism by impeding the synthesis of muscle proteins. It also sensitizes smooth vascular musculature to catecholamines, making for better blood supply to the working muscles.
The thyroid hormones are important for the body’s metabolism and for the growth and development of children.
Synthesis of thyroid hormones
The thyroid cells synthesize thyroglobulin, which contains a lot of tyrosine molecules. Via the addition of iodine atoms, they become triiodothyronine T3 or tetraiodothyronine T4. This is the form in which it is stored in the thyroid follicles.
For the liberation of T3 and T4, thyroglobulin is split off. Some T4 is transformed into T3 in the blood. Most T3 is therefore formed outside the thyroid gland.
Stimuli for the secretion of thyroid hormones
The thyroid gland is a part of the HPA. The TRH of the hypothalamus releases TSH within the anterior lobe of the pituitary gland. In turn, this hormone stimulates the production of T3 and T4. Both have a negative feedback effect on the hypothalamus and the pituitary gland.
Thyroid hormones receptors and effects
Like the steroid receptors, the receptors for the thyroid hormones are located in the nucleus. When activated, they enhance the expression of certain genes. This affects numerous proteins and enzymes. Overall, the thyroid hormones cause an increase in energy turnover.
The sex hormones estrogen, progesterone, and testosterone are also regulated by the HPA axis. The hypothalamus liberates a releasing-hormone, the GnRH. The pituitary gland then releases FSH and LH, which stimulate hormone production in the gonads. Testosterone production is regulated by LH.
Prolactin is also produced within the anterior lobe of the pituitary gland. Its liberation is both inhibited by the prolactin-inhibiting hormone, and promoted by TRH and by stress. It is a peptide hormone and it promotes growth and differentiation of the mammary glands. It also inhibits the release of LH and FSH, and influences the immune system.
These hormones influence the gastrointestinal tract in several ways. They regulate intestinal motor function, digestive secretions, and feedback to the central nervous system (CNS). The gastrointestinal system has not yet been thoroughly investigated. Only the most important hormones are presented below.
Synthesis of gastrointestinal hormones
Almost all gastrointestinal hormones are peptides, which are synthesized and secreted by different cells throughout the enteral system. They act by both endocrine and paracrine pathways.
Effects of gastrointestinal hormones
Gastrin is produced and liberated by the G-cells in the antrum and the duodenum. It acts via the G protein-coupled (cholecystokinin B) CCKB-receptor and the ensuing phospholipase C.
On the 1 hand, gastrin directly stimulates the production of gastric acid in the parietal cells. On the other hand, it releases histamine from the enterochromaffin-like (ECL)-cells, which in turn activates adenylate cyclase in the parietal cells via the H2-receptor, and increases acid production. Gastrin also stimulates the release of pepsinogen and other digestive secretions.
The release of gastrin is stimulated by the vagal nerve, distension of the gastric wall, peptides, alcohol, caffeine, and by an increase in pH.
Secretin is secreted into the duodenal blood by the S cells and it has an antagonistic effect with respect to gastrin. On the 1 hand, it inhibits gastrin and gastric acid production. On the other hand, it promotes the secretion of bicarbonate and water by the pancreas, the bile ducts, and the small bowel. It is stimulated by a pH of less than 4.
Cholecystokinin (CCK) is produced in the duodenum and jejunal I cells. Like secretin and gastrin, it is a peptide hormone. It binds to CCKA- and CCKB-receptors in the pancreas. Both are Gq-protein-coupled receptors, which cause an increase in intracellular calcium concentration when activated.
This results in more digestive enzymes being liberated from the vesicles, aiding overall digestion and additionally aiding contraction of the gallbladder and the sense of satiety. The release of CCK is stimulated by the products of protein degradation and by lipids in food.
Calcium phosphate balance
The various regulators affecting calcium balance and the functions of these regulators must always be considered in relation to the whole body. There are 3 hormones with synergistic effects that are only employed when there is a lack of calcium. This section is therefore organized so as to reflect these 3 hormones.
1. Parathyroid hormone (PTH):
PTH is released from the parathyroid glands when the levels of calcium are low. It stimulates osteoclasts, i.e. osteolysis, and also the liberation of calcium into the blood. It additionally increases phosphate excretion and inhibits calcium excretion within the kidney. The release of calcitriol is stimulated as well.
Calcitriol (1,25-dihydroxycholecalciferol or 1,25- dihydroxy vitamin D3, the hormonally active metabolite of vitamin D) is formed in the kidneys from vitamin D, which needs to be ingested. Calcitriol increases the absorption of calcium in the intestine.
Calcitonin is released by the thyroid gland’s C cells when there is an acute oversupply of calcium, e.g., as a consequence of undersupply. It inhibits osteoclasts and promotes the incorporation of phosphate into the bones. It also has an antagonistic effect with respect to calcitriol and inhibits the absorption of calcium in the intestine.