Hormonal Action: How Hormones are working in Animals

• Adrenal Hormones : Glands and its Secretions
• Pituitary Gland and its Secretions
• Peptide hormones: Pancreatic secretions – 1
• Insulin: Pancreatic Peptide Hormone -2

Hormonal Action: How Hormones are working:

a) Hormones with cell surface receptors and Peptide Hormone Mechanism

b) Hormones with intracellular receptors (or) Steroidal Hormone Mechanism

a. Peptide Hormonal Action and its mechanism:

Hormonal Action: Hormones with cell surface receptors (or) Peptide Hormonal mechanism

Cyclic AMP:

• Cyclic AMP was first discovered by “Earl.W.Sutherland” & “T.W.Rall” in 1960, who was awarded Nobel prize in 1971.
• “Adenyl cyclase(AC)” converts ATP to cAMP (3’,5’-Cyclic AMP) and “Phosphodiesterase” hydrolyzes cAMP to 5’AMP.
• Cyclic AMP acts as an intracellular hormonal mediator.
• The cAMP is also frequently referred to as the Second messenger for hormone mediation; the first messenger being the original hormone itself.

G-Protein (or) Nucleotide Regulatory Protein:

• “Alfred G.Gilman” and “Martin Rodbell” are awarded Nobel prize in 1994 for their work on G-Protein.
• The G-Protein is a peripheral membrane protein consisting of alpha, beta and gamma sub units.
• When GTP is attached, it becomes active. Then it can activate the “Adylate cyclase”.

G-Protein activates Adylate Cyalse:

When the Hormone – Receptor complex is form, the activated receptor stimulates the G-protein, which carries the excitation signal to adenylate cyclase. This signal transduction takes place in the plasma membrane. The adenylate cyclase is embedded in the plasma membrane.

Mechanism of Hormonal Action:

The extracellular messenger, the hormone (H) combines with the specific receptor (R) on the plasma membrane. The H-R complex activates the regulatory component of the protein designated as G-protein (or) nucleotide regulatory protein.

G-proteins are so named because they are bound to GTP. The binding of hormone to the receptor triggers the exchange of GTP for bound GDP. The H-R binds to the G-protein, induces the release of bound GDP & allows GTP to bind. The alpha sub unit, which binds the GTP, dissociates from the beta-gamma sub units.

The activates G-alpha-GTP activates the adenylate cyclase (AC) that is exposed to the cytoplasm causes immediate conversion of cytoplasmic ATP into cAMP. The cAMP then acts inside the cell to initiate a number of cellular functions before it itself is destroyed.

The cAMP elicits many of its effects by activating protein kinases. These kinases are a tetrameric molecule having 2 regulatory (R) and 2 catalytic sub units’ (R₂C₂). This complex has no activity. But cAMP binds to the regulatory and catalytic sub unit and catalytic sub units.

The catalytic sub unit then transfers a phosphate group from ATP to different enzyme proteins. Phosphoryl1ation usually takes place on the –OH group Serine, Threonine (or) Tyrosine residues of the substrates. The enzymes may be activated (or) inactivated by this phosphorylation.

Some important hormone responsive protein kinases:

• Calmodulin-dependent kinase
• cAMP-dependent kinases-I & II
• cAMP –dependent kinase
• Epidermal growth factor-dependent tyrosine kinase
• Insulin-dependent tyrosine kinase
• Pyruvate dehydrogenase kinase
• Phosphorylase kinase

Other actions of cAMP are summarized below:

• cAMP helps in conversion of cholesterol in pregnenelone.
• It stimulates 11-beta hydroxylase for catecholamine synthesis.
• It stimulates tyrosine hydroxylase for catecholamine synthesis.
• It stimulates melatonin synthesis by increasing N-acetyl transferase of pineal gland.
• It causes the release of insulin from pancreatic islet cells.
• Histamine stimulates production of gastric HCl through cAMP.
• It induces cells to differentiate.

Mechanism of action of certain toxins:

a) Cholera:

• The toxin binds to a ganglioside on intestinal mucosal cell, which leads to ribosylation of the alpha subunit of Gs-Protein.
• This results in the inhibition of the inherent GTPase activity and irreversible activation of G-Protein.
• Therefore Adenylate cyalase remains active and keeps cAMP level high.
• This prevents absorption of salts from intestine leading to watery diarrhea and loss of water from body.

b) Pertusis:

• The toxin irreversibly activates adenylate cyclase by promoting the ADP ribosylation of G-ai, which prevents the G-aI sub unit from being activates.

c) NaF:

• It is another irreversible activator of cyclase.

b. Steroidal Hormonal Action and its Mechanism:

Hormonal Action : Hormones with intracellular receptors (or) Steroidal Hormone Mechanism

The hormones in this group include the steroidal hormones and thyroidal hormones. They diffuse through the plasma membrane and bind to the receptors in the cytoplasm. The Hormone – Receptor (HR) complex is formed. The complex is then translocated to the nucleolus. The HR binds to promoter (or) regulatory elements of the DNA and activated (or) inactivates genes.

The hormone binds to the specific area of the genes, referred to as the “Hormone Responsive Element (HRE)”. Steroid hormone receptor proteins have a molecular weight about 80 to 100KD. Each monomer binds to a single steroid molecular at a hydrophobic site but on binding to genes they dimerizes.

The receptor bind by virtue of their DNA binding capacity. The steroid regulated genes have “Steroid receptor binding sites” (or) “Steroid response elements (SREs)”. The SRE acts as an enhancer element and when stimulated by hormone, would increase transcriptional activity. Binding to the SRE sequence leads to dimerization of the receptor.

Simply, the sequence of events is as follows:

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 nucleolus, where it reacts with the nuclear chromatin.
3. Some 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 mRNA in the nucleolus.
5. The mRNA diffuses into the cytoplasm where it accelerates the translocation process at the ribosome to synthesize new proteins.