Hormones and Receptors
Hormones and Receptors
Definition: chemicals produced by the body that elicit cellular responses to regulate physiologic processes, often involving feedback mechanisms. They are either endocrine or exocrine, which is generally dependent on the gland that secretes them:
- Endocrine: hormone is released directly into the bloodstream.
- Exocrine: hormone is released into a duct system or a lumen, such as the GI tract.
CLASSES OF HORMONES
There are other types, such as purines (i.e., adenosine) and vitamin derivatives (i.e., 1,25-dihydroxycholecalciferol and retinoids). Additionally, there are important signalling compounds that are similar to hormones, but do not fulfill the true definition, such as neurotransmitters, eicosanoids and most growth factors.
Meticulous coordination between organ systems is required to sustain homeostasis. Homeostasis is, therefore, dependent on cell comminication. Specifically regarding hormones, this cell-to-cell signalling occurs through several ways:
- Endocrine: proceeds through the release of the hormone into the blood to signal at distant cells.
- Paracrine: the signal is to local cells.
- Autocrine: the signal is targeted at the cell that released it, often going hand-in-hand with paracrine signalling.
HORMONES IN PLASMA
Just how much hormone can get into the tissues and occupy the corresponding receptors depends on the concentration of free hormone in the plasma, which is dictated by three main factors:
- The rate of synthesis and secretion of the hormone.
- The rate at which the hormone is eliminated (usually in urine or bile, or it can be internalised and degraded in the target cell) once in the plasma.
- How much of the hormone is plasma protein-bound. Hormones cannot diffuse into tissues if they are bound to a protein; they must dissociate from the protein first.
Since the steroids and thyroid hormones are highly protein bound in plasma, they tend to have longer half-lives than the peptides and catecholamines.
REGULATION OF HORMONE RELEASE
The key term here is: negative feedback. Much of endocrinology revolves around this principle.
Direct negative feedback occurs when a hormone, or the effects of a hormone, inhibits its' own secretion. This process of regulation is commonplace in physiology, occuring with hormones such as insulin and glucagon.
However, for hormones that are dependent on the tropic hormones from the anterior pituitary gland for secretion, a more complex process occurs. In this case, secretion is controlled by a series of regulatory stages:
- Promoting target hormone secretion: hypothalamic releasing factors (i.e., CRH) stimulate pituitary tropic hormone (i.e., ACTH) secretion, which in turn stimulate target hormone (i.e., cortisol) secretion from the target gland (i.e., adrenal cortex).
- However, the target hormone exerts an inhibitory effect on the secretion of hypothalamic releasing factors and pituitary tropic hormones, thus regulating its own rate of secretion. In addition, the tropic factors inhibit releasing factor secretion.
This is the foundation of negative feedback.
Each pathway including a hypothalamic releasing factor, anterior pituitary tropic hormone and an effector gland is called an axis (i.e., the hypothalamic-pituitary-ovarian axis).
There are circumstances in which the regulation of secretion is under positive feedback control. Here, the hormone produces the effect of further increasing hormone secretion rather than inhibiting secretion. For instance in the menstrual cycle, the surge of LH that induces ovulation is caused by oestrogen sensitising the anterior pituitary gland to GnRH and thus increasing its secretion of LH. This is positive feedback.
Receptors are molecules that hormones bind to in order to exert their effects. They are broadly classified into two divisions: membrane receptors and nuclear receptors.
The membrane receptors are primarily activated through the binding of peptide hormones and catecholamines.
The ligand (hormone), or first messenger, binds to its corresponding receptor and elicits the activation of a second messenger system, which is mediated with intracellular signalling molecules (often involving a series of phosphorylation reactions). The second messenger system amplifies the signal initiated by the hormone.
- G protein-coupled receptors
G protein-coupled receptors (GPCRs) span the membrane seven times, with the receptor exposed extracellularly and regions that activate a G protein intracellularly. The G proteins are made up of three components: α, β and γ subunits.
Ligand binding to the receptor results in a conformational change that causes the α subunit to exchange a GDP molecule for that of a GTP molecule. This causes the GTP-bound α subunit to dissociate from the βγ complex and act at an effector (usually an enzyme, but sometimes an ion channel or other protein). The α subunit hydrolyses GTP back to GDP to terminate the process.
Cyclic adenosine monophosphate (cAMP) as a second messenger:
There are stimulatory GPCRs that have an α subunit that activates adenylate cyclase, an enzyme that converts ATP to cAMP. cAMP is an important second messenger molecule that activates a protein kinase, which sets a phosphorylation cascade in motion to produce the effects of the ligand. A similar class of GPCRs are inhibitory and prevent the activation of adenylate cyclase.
A class of enzymes called phosphodiesterases degrade cAMP to halt the response in the stimulatory GPCRs.
Diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3) as second messengers:
Some more stimulatory GPCRs have an α subunit that activates phospholipase C, which cleaves phospholipids into important signalling molecules: DAG and IP3. IP3 mobilises calcium from the sarcoplasmic reticulum. This increase in intracellular calcium alters the activity of many proteins and facilitates the activation of a protein kinase by DAG, thus initiating a phosphorylation cascade. The effects come about due to the elevated calcium (which has a wide range of potential effects) and the phosphorylation cascade.
Examples of GPCRs: adrenergic receptors, FSH receptor, dopamine receptors, glucagon receptor, angiotensin II receptors.
- Kinase-linked receptors
These receptors have an extracellular ligand-binding site, traverse the membrane and attach to a kinase (usually a tyrosine kinase). When a ligand binds, the receptor undergoes a conformational change that induces autophosphorylation of the kinase. The kinase then sets off a phosphorylation cascade that results in alterations in gene expression and protein activity. Insulin, growth hormone and many cytokines signal through this way.
All nuclear receptors act to change the degree of gene expression, however some are primarily located in the cytoplasm (i.e., those for the steroids) and some are always located in the nucleus (i.e., those for the thyroid hormones).
- Steroid receptors
The steroid diffuses through the membrane and binds to its nuclear receptor in the cytoplasm. It then dissociates from chaperone proteins and translocates to the nucleus, where another steroid-receptor complex binds to it to form a dimer of steroid-receptor complexes, which exposes the DNA-binding site and, at this point, becomes active. This active site binds to positive (increasing transcription) or negative (decreasing transcription) steroid response elements on the target genes.
- Thyroid hormone receptors
The thyroid hormone receptors are already dimerised in the nucleus and bound to the target genes. There are inactivating chaperone proteins that dissociate once the hormone has bound, allowing the dimer of hormone-receptor complexes to initiate changes in gene expression at the thyroid response elements.
SOURCES AND REFERENCES
- J. Kibble, C. Halsey; Medical Physiology: The Big Picture; illustrated edition; McGraw Hill, 2009; p. 307-316
- D. Golan et al.; Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy; 2nd edition; Lippincott Williams & Wilkins, 2008; p. 8-15, 485-486
- M. Neal; Medical Pharmacology at a Glance; 6th edition; John Wiley and Sons, 2009; p. 8-9
- A. Fauci et al.; Harrison's Principles of Internal Medicine; 17th edition; McGraw-Hill Medical, 2008; p. 2187-2195
- K. Barrett et al.; Ganong's Review of Medical Physiology; 23rd edition; McGraw-Hill Medical, 2009; p. 50-59