Mechanisms Of Hormone Actions

Hormones have an incredible regulatory effect and can lead to physical and mental changes in the body. Mechanisms of Hormone Actions is a crucial topic for Physiology paper. 

Read this post till the end to scale up your Physiology preparation for NEET PG.

• Hormones are defined as chemical substances having specific regulatory effects on the activity of an organ or organs. The term hormone was originally applied to substances secreted by various endocrine glands and transported in the bloodstream to various target organs. It means that hormones are cell signaling molecules.

Cell Signaling

There are different types of cell signaling molecules:

• Endocrine
• Autocrine
• Paracrine
• Juxtacrine

Endocrine Cell Signaling

• In the endocrine type of cell signaling, the chemical substances produced by the gland enter the bloodstream through fenestrated capillaries in the body and travels further to reach various target organs or cells that act as receptors. Examples of endocrine hormones include: Thyroid stimulating hormone, T3, T4, etc.

Autocrine Cell Signaling

• In this type of cell signaling, the chemical substances act on secretory cells themselves. Here the receptors are present in the same cells of production.

E.g.

• PAF (Platelet-activating factor) is produced from platelets and acts on the same platelets for activation and degranulation, followed by the aggregation of the platelets. The beta-cell of the pancreas produces Insulin which acts on the same cells for further release.

Paracrine Cell Signaling

• In the paracrine type of cell signaling, the chemical substances a secretory cell produces reach the adjacent target cell, where the receptor is present, with the help of diffusion.

E.g., 

• Somatostatin, produced by the D-cells in GIT (gastrointestinal tract), inhibits acid secretion from the parietal cell by acting on it. Histamine, produced from the entero-chromafin-like cell (ECL) in the stomach, stimulates acid secretion from the parietal cells.  D-cell mediated paracrine signaling is also present at the level of islet cells of the pancreas. 

Juxtacrine Cell Signaling

• In the juxtacrine type of cell signaling, the cells that produce the chemical substance and the cells on which their receptors are present are in such close contact that the lie end expressed by the secretory cell and the receptor cell interact directly with each other. It also happens as the plasma membranes of these cells are very adjacent to one another. Here diffusion is not taking place. E.g., Transforming growth factor-alpha (TGF-alpha) is a typical example.

Regulation of Hormone Secretion

• The feedback control or the rhythmic control regulates hormone secretion. There are two types of feedback control for the regulation of hormone secretion. They are
  • Negative feedback control or loop. E.g., ACTH, TSH, etc. Positive feedback control or loop. E.g., LH surge and ovulation.

Certain rhythmic controls are also present for the regulation of hormone secretion. They are

• Ultradian rhythm
  • Any biological activity or rhythm with cyclicity of less than 24hr revisions is called ultradian rhythm.
    E.g.,
    • ACTH secretion has multiple small peaks during the day (which is not the highest). But the interval between these is less than 24hr. The control of food intake is also an example of ultradian rhythm since the interval between two meals is less than 24hr.
• Circadian or diurnal rhythm
  • Any biological activity or rhythm with cyclicity of exactly 24hr revisions is called Circadian rhythm. 
    E.g.,
    • ACTH secretion peaks at almost 8 am and is at its lowest midnight period. This again peaks at about 8 am the next day.  The sleep-wake cycle is the simplest example of a circadian rhythm. When this circadian rhythm is associated with the light-dark cycle, it is called a Diurnal rhythm.
• Infradian rhythm
  • Any biological activity or rhythm with cyclicity of more than 24hr revisions is called infradian rhythm. 
    E.g., 
    • The most typical example is the menstrual cycle which has a cyclicity of 28-30 days.

Types of Hormones

• It is essential to understand the different types of hormones in the body to understand the mechanism of hormone action and regulation. The different types of hormones in the human body are:
• Steroids
  • These hormones are secreted from cholesterol as the raw material. After the synthesis, they are not stored within the cell but instead released into the bloodstream. E.g., Glucocorticoids, Mineralocorticoids, Androgens, Estrogen, progesterone, etc.
• Amino acid derivatives
  • These are the hormones derived from amino acids.  E.g., Catecholamines and thyroid hormones (from tyrosine), serotonin (from tryptophan) 
• Peptide and protein derivatives
  • These hormones are synthesized from a rough endoplasmic reticulum (RER) as a long peptide called pre-pro-hormones. The pre-pro-hormones are fragmented into parts and packed into vesicles by Golgi bodies, which are then stored in the cell itself. Once the cell receives a stimulus, it releases its content into the blood. E.g., Pituitary, pancreatic, parathyroid hormones, erythropoietin, etc.
• After entering the blood, steroidal hormones require some binding protein or carrier protein for transport inside blood from one part to the other, as they don't get mixed up with the water portion of the plasma. As these hormones are attached to a binding protein, the t_1/2 or half-life of these hormones is long. About 90% of the steroidal hormones remain in this complex form. The remaining 10% remains free in the plasma. For example, the t_1/2 of the T₄ hormone is 7 days. So the filtration and clearance of the hormone are not simple. Protein hormones mainly remain free in the plasma. As a result, the t_1/2 of protein and peptide hormones are short. For example, the t_1/2 of the insulin hormone is only 5 mins.
• Although thyroid hormones are put under the category of amino acid derivatives, it is steroidal. It possesses several properties of steroidal hormones like the ability to cross biological membranes, the presence of receptors inside the cell, etc...

Q. What is the main factor that influences the T_1/2 of a receptor?

A. Binding protein

Hormone Receptor

Protein Hormone Receptor Activity

• When a protein hormone approaches a biological cell, it cannot penetrate through the cell's plasma membrane. So the hormone receptor must be present at the level of the plasma membrane to function properly. Once the hormone attaches to the receptor, receptor activation takes place, leading to the generation of a second messenger system. With the help of the second messenger system, the hormone acts by causing the phosphorylation of various enzymes in the cell.

Steroidal Hormone Receptor Activity

• A steroidal hormone easily crosses the plasma membrane via simple diffusion and enters the cytoplasm. The hormone then attaches to the receptor at the cytoplasm level, or it further crosses the nuclear membrane and enters into the nucleus, where it attaches to the receptor present there. Even if the hormone attaches to the receptor at the cytoplasm level, it should travel further and enter into the level of the nucleus because the action of steroidal hormones is mainly at the level of expression of genes. When the hormone receptor attaches to a particular portion of the gene, it causes gene expression. This kind of action of the steroidal hormone is called the genomic action of the steroidal hormone. 
• Certain steroidal hormones also express non-genomic action. For example, the estrogen hormone, apart from its normal functions, also causes vasodilatation at the level of cerebral vessels and other parts. This action of estrogen is also rapid compared to the genomic action of steroidal hormones, which are comparatively slow. This was explained by discovering mineral receptors of a few steroidal hormones on the plasma membrane. The hormones enter the cell through these plasma receptors and produce a particular kind of second messenger-like. In the case of estrogen, the MAP Kinase pathway is activated and causes rapid action of hormones, also called the non-genomic action of the steroidal hormone. Other hormones like testosterone and aldosterone also have non-genomic action. At times on the plasma membrane or in the cytoplasm, certain receptors are present which are structurally similar to other receptors. Still, the ligands of the same haven’t been discovered yet. Such receptors are called orphan receptors. If the receptor's ligand is discovered sometime in the future, it would be called an adopted orphan receptor.

Hormone Receptor Classification

• Based on the location, the receptors are of different types, like membrane receptors, intracellular receptors, etc.

Membrane Receptors

• The hormones that have membrane-bound receptors are subdivided into 5. They are:
  • G-protein coupled receptor (GPCR)
  • Guanylyl receptors
  • Tyrosine kinase receptors
  • Cytokine receptors
  • Serine kinase receptors
• The hormones that are of intracellular receptors are either cytoplasmic or nuclear:
  • Cytoplasmic: Growth hormone, mineralocorticoid, estrogen, androgen, progesterone. Nuclear: Thyroid, Vit-D, Retinoic acid receptor (RAR, RXR)

Q. Which scientists were awarded the Nobel prize for the discovery of G-protein?

A. Alfred G. Gilman and Martin Rodbell

G-Protein Coupled Receptor (GPCR) Mechanism

• The G-protein in its resting state has 3 subunits which are alpha, gamma, and beta. Hence it is also called Heterotrimeric G-protein. It is also bound to either guanosine triphosphate or guanosine diphosphate or could be said as a guanine-binding protein. So it is called G-protein. The G-protein in resting condition is characterized by the following:

• Does not interact with the receptor even though it isn't much distant from the G-protein. It is attached to the cell membrane with the help of lipid chains. The beta sub-unit has no direct interaction with the plasma membrane. On the other hand, the gamma and alpha sub-units have direct interaction with the plasma membrane. The G-protein is also attached to the Guanosine Diphosphate (GDP).

• When a hormone approaches the receptor and attaches to the upper part of the receptor, there will be some changes in the conformation of the receptor. Due to the changes in the receptor, it attracts the G-protein towards it. The G-protein moves towards the receptor and begins to interact with it. Upon this interaction, the inactive state of the G-protein changes into an active state. As a result, the Guanosine Diphosphate molecule (GDP) will be replaced with the Guanosine Triphosphate molecule (GTP). When the activation occurs, and G-protein receives the GTP, the alpha sub-unit has a lesser affinity towards the beta and gamma sub-units than before. Due to this reason, the alpha sub-unit and the GTP detach from the beta-gamma sub-unit and move towards the effector molecule, as shown in the image.

• There are two probable chances for the effector molecule. It would be either adenylyl cyclase or phospho-lipid C.

• Upon stimulation of the effector molecule, a second messenger will be produced, which will act like the hormones by generating a downstream pathway. The second messenger will perform the phosphorylation of proteins inside the cell and the activation of enzymes, eventually leading to the ultimate act of hormones. In the case of the need for inactivation for the G-protein, the alpha sub-unit performs an intrinsic GTPase activity which causes the breakdown of the GTP molecule into a GDP molecule. This also increases the affinity of the alpha sub-unit towards the beta-gamma sub-units. Now the alpha sub-unit moves towards the beta-gamma sub-units. Thus it once again forms a complete G-protein. But since the hormone is still attached to the receptor molecule, it could attract the G-protein towards it. This needs to be terminated. To terminate the hormone, the phosphorylation of the active receptor is done by the G-receptor kinase molecule (GRK). This is the first step of inactivation. After that, the Arrestin molecule moves towards the receptor, binds with the receptor, and blocks it completely. When the receptor is blocked, it will not interact with the G-protein, even if the hormone is attached. This is the final step of inactivation. The failure to terminate the inactivation of the receptor can lead to cell destruction. This is typically seen if there is a mutation in GR Kinase. Once such failure to terminate the activity of rhodopsin molecules causes continuous activation of rod cells, which leads to the death of receptor cells in the retina, causing a condition called Retinitis Pigmentosa.

G-Protein Coupled Receptor Mechanism Effectors

• The GPCR has two effectors, which are adenylyl cyclase and phospholipase C.
  • The G-protein that activates the adenylyl cyclase is called GS or stimulatory G-protein. The G-protein that inhibits the adenylyl cyclase is called GI or inhibitory G-protein. The G-protein that stimulates phospholipase C (PLC) is called Gq. Another G-protein exists, which is G12/13, whose function is unknown. This classification is based on the alpha sub-unit as it acts on the effector molecule.
• When the adenylyl molecule is activated, the cAMP level will be high and decrease when inhibited. This cAMP is the second messenger for the Adenylyl cyclase effector. The CAMP causes the activation of an enzyme called protein kinase A (PKA) which causes the phosphorylation of other proteins in the cell that could be enzymes of various metabolic pathways (main action). 
  • In certain cells, the protein kinase A can enter the nucleus and bond with the CREB molecule (cAMP response element binding protein). This can cause gene transcription and gene expression. This is not usually common for the GPCR. This action takes place in certain areas like the hippocampus for the formation and consolidation of memory.

• The second messenger for the effector PLC would be IP₃ and DAG.
  • The DAG or diacylglycerides activates protein kinase C (PKC), leading to phosphorylation and hormone activation.  IP3 or inositol triphosphate (has a receptor at the endoplasmic reticulum level) causes the flow of the Ca++ from the endoplasmic reticulum to the cytoplasm. A Ca-Calmodulin complex is formed that activates the kinase molecule called Ca-Calmodulin dependent kinase, which causes phosphorylation and thus hormone action.
• The hormones that come under the GPCR are given in the table below.

Q. What condition results from the failure to terminate the activity of rhodopsin molecules in the retina?

A. Retinitis Pigmentosa

Guanylyl Cyclase Receptor Mechanism

• Certain hormones like ANF (Atrial natriuretic factor), Nitric oxide, and the guanylyl cyclase receptor are activated. This results in an increase in cGMP. Followed by this, the activation of cGMP-dependent kinase molecules takes place. This results in the phosphorylation of the intracellular proteins, and finally, the effects of hormones occur.

Receptor Tyrosine Kinase Mechanism

• The tyrosine kinase and the cytokine have a tyrosine kinase domain in the intracellular part of the receptor.  The serine kinase has a serine kinase domain in the intracellular part of the receptor.  Whenever a hormone is attached to any of these 3 kinds of receptors, they attach close to one another and form a dimer (dimerization occurs). Post dimerization, the tyrosine kinase domain gets activated in the tyrosine kinase receptor variety, and cross-auto-phosphorylation of the receptors occurs. Apart from this, phosphorylation of various intracellular proteins is also done. If they are phosphorylating proteins like AKT, and MAPKinase pathway, the hormones acting here are Insulin and IGF-1.
  • If they are phosphorylating proteins like Ras, Raf, and MAPKinase pathway, the hormones acting here are EGF (epithelial growth factor) and NGF(Nerve growth factor).
• This kind of auto-phosphorylation is not seen in cytokine receptors or serine kinase receptors. In cytokine receptors, there will be direct phosphorylation of intracellular proteins, which is activated, i.e. The JAK-STAT pathway, The hormones that act through this are Growth hormone, Prolactine. In the serine kinase receptor, the domain contains serine kinase activity. There will be direct phosphorylation of intracellular proteins, which is activated, i.e. the SMAD pathway. The hormones that act through this are Mullerian Inhibiting substances (MIS), Activin, etc.

 A summary of various hormone receptors, their second messengers, and hormones is given in the following table.                              

 A summary of various hormone receptor mechanisms is given in the image below.

Steroidal or Intracellular Hormone Receptors

• Since steroidal hormones are lipophilic, they can easily cross the cell membrane through diffusion. nce they enter the cytoplasm, they will bind to the cytoplasmic receptor or travel to the nucleus to attach to the nuclear receptors. Either way, the hormone receptor complex would ultimately be delivered at the nucleus level. Here perform their gene expression regulation. If the receptor is present at the level of cytoplasm, then it is called Type-1 steroidal hormone.  In the cytoplasm, these receptors are attached to a molecular chaperon called HSP or Heat Shock Protein. They help in folding and covering the receptor in the absence of hormones. When the hormone enters the cytoplasm, the HSP is released, and the hormone binds to the receptor to form the hormone receptor complex. They undergo dimerization to form a homodimer. They are then delivered into the nucleus. They attach to a particular DNA part and carry out the gene expression. In Type-2 steroidal hormones, the receptor is already inside the nucleus and attached to the DNA.
• Here the receptor is attached to a molecule RXR, and in the absence of a ligand, it is also attached to a corepressor molecule. This corepressor molecule inhibits gene expression. Whenever the hormone enters the nucleus and attaches to the receptor, the corepressor molecule will be removed.  The heterodimer is readily attached to the DNA. It takes the help of various Co-activator molecules to carry out gene expression. Examples of homodimer receptors are estrogen, androgen receptor, progesterone receptor, and growth hormone receptor. Examples of heterodimer receptors are the thyroid hormone receptor, Vit-D receptor, Peroxisome proliferator-activated receptors (PPAR), and Vit-A receptor.

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