LECTURE NOTES ON MECHANISM OF HORMONE ACTION

Mechanism of action of lipid soluble(steroid) hormones. Lipid soluble hormones enters the cell  cause synthesis of proteins in the target cell. These proteins are presumably the enzymes which, in turn, activate other functions of the

cells.

1. The steroidal hormone enters the cytoplasm of the target cell where it binds with a specific, high- affinity receptor protein.

2. The receptor protein- hormone complex, so formed, then diffuses into (or is transported into) the nucleus, where it reacts with the nuclear chromatin.

3. Somewhere along this route, the receptor protein is structurally altered to form a smaller protein with low molecular weight. Or else the steroid hormone is transferred to a second smaller protein.

4. The combination of the small protein and hormone is now the active factor that stimulates the specific genes to form messenger RNA (mRNA) in the nucleus.

5. The mRNA diffuses into the cytoplasm where it accelerates the translation process at the

ribosomes to synthesize new proteins.

Example, the aldosterone, one of the mineralocorticoids secreted by adrenal cortex, enters the cytoplasm of the renal tubular cells. These tubular cells contain its specific receptor protein and hence above sequence of events follows. After about 45 minutes, the proteins begin to appear in the renal tubular cells that promote sodium reabsorption from the tubules and potassium secretion into the tubules. This characteristic delay, of about 45 minutes, in the final action of this steroid hormone is in marked contrast to the almost instantaneous action of some of the peptide hormones.

Mechanism of action of thyroid hormone:

The mechanism of action of thyroid hormones is similar to that of steroid hormones. They act by binding with the intracellular receptors. With few exceptions like adult brain and gonads, receptors for thyroid hormones are present in all tissues and organs. Though the developing neurons in infants and children are highly sensitive to thyroid hormones, it is not clear why the adult neurons are not so sensitive.

The steps of mechanism of action are as follows:

1. T3 and T 4 enter the cells of the target organs by carrier mediated (energy dependant) transport.

2. lnside the cell, most of the T4 is converted to T3, which then binds with the thyroid-hormone receptors (TR) present on nucleus. The thyroid receptor protein is bound to thyroid-hormone response elements (TRE) in the DNA via Zinc fingers.

3. Binding of T3 with thyroid hormone receptor-TRE elements causes translation of DNA that in turn  increases the transcription of mRNA .

4. Increased mRNA causes increased intracellular protein synthesis that stimulates cellular growth and maturation, increases intracellular enzyme synthesis, increases mitochondria formation and respiratory enzyme synthesis, and increases Na⁺-K⁺ATPase activity.The increased Na⁺-K⁺ATPase activity increases cellular oxygen consumption and increased mitochondrial activity increases general metabolism of the cell.

Mechanism of action of insulin

Insulin acts on insulin receptors present on various cells.The major target tissues of insulin are liver, skeletal muscle and adipose tissues.

Insulin Receptor

Insulin receptor (IR) is a glycoprotein tetramer consisting of two µ and two ,ß subunits. The µ  subunits are present on the membrane extracellularly, whereas the ß subunits traverse the membrane. Thus, ß subunits have extracellular domain, membrane domain, and intracellular domain . The µ and  ,ß subunits are glycosylated. They are bound to each other by disulfide bridges.

Steps

Insulin binding to its receptors trigger following events:

1. The binding of insulin to µ subunits brings about conformational change in the ß subunits.

2. The intracellular domain of ß subunits possesses tyrosine kinase activity. Conformational change of  the ß subunits activates its tyrosine kinase activity. This produces autophosphorylation of ß subunits on tyrosine residues.

3.Autophosphorylation triggers phosphorylation of many intracellular proteins that alter cell functions. Dephosphorylation of proteins also occurs.

4.The active tyrosine kinase phosphorylates tyrosines on insulin receptor substrates (IRS 1 and IRS2). IRS proteins are docking proteins to which a variety of downstream proteins bind. Thus IRSphophotyrosines serve as docking site and activating site for different protein kinases and protein phosphatases . The IRS also serves as facilitatory proteins that link to membrane G proteins, phospholipases, and ion channels.

5.Phosphorylation of IRS causes activation or deactivation of many target enzymes, translocation of GLUTs (glucose transport proteins) to the cell membranes and induction or suppression of genes in the nucleus. This results in synthesis of different intracellular proteins.

6.GLUT 4 move to the cell membrane facilitates glucose entry  into the cell. The insertion of different protein channels on the plasma membrane increases entry of  amino acids, potassium, magnesium, and into the cell. Activation of mitogenic proteins Increases  transcription of various factors that are essential for stimulation of gene expression, especially concerned with cell growth.

When epinephrine stimulates its target organs. it must first bind to adrenergic receptor proteins in the plasma membrane of its target cells. There are two types of adrenergic receptors—alpha and beta. Stimulation of the beta-adrenergic receptors by epinephrine results in activation of adenylate cyclase and the production of Cyclic AMP.

Stimulation of alpha-adrenergic receptors by epinephrine, in contrast activate the target cell via the Calcium second-messenger system .The binding of epinephrine to its alpha-adrenergic receptor activates, via G-proteins, an enzyme in the plasma membrane known as phospholipase C . The substrate of this enzyme, a particular membrane phospholipid is Split by the active enzyme into inositol triphosphate[IP3] and another derivative, diacylglycerol . Both derivatives serve as second messengers.

The IP3, leaves the plasma membrane and diffuses through the cytoplasm to the endoplasmic reticulum. The membrane of the endoplasmic reticulum contains receptor proteins for lP3.This binding of IP3 to its receptors causes specific Ca channels to open. so that Ca diffuses out of the endoplasmic reticulum and into the cytoplasm .

As a result of these events. there is a rapid and transient rise in the cytoplasmic Ca+ concentration. This signal is amplified by the opening of Ca+ channels in the plasma membrane. This may be due to the action of a messenger sent from the endoplasmic reticulum to the plasma membrane. The Ca promotes the hormonal effect in the target cell.