Hormones and their signal

Hormones are chemical substances secreted by special cells to regulate the metabolic functions of other cells.

Hormones pass through blood to reach target tissue where they cause their effect when they bind to their specific receptors found on target tissues.

Hormones receptors: are protein molecules where the hormones bind.

They have 2 functional sites:

1.      Recognition site: it binds specific hormone.

2.      Signaling site: it couples hormone binding to intracellular effect.

Types of receptors:

  

Nuclear receptors present in nucleus and there is direct association with one or more chromosomes.

Ex: thyroid hormone and Vitamin D.

Cytoplasmic receptors present in cell cytoplasm. Ex: Steroid hormone.

Membrane receptors present on surface of cell membrane.

There are 3 types of this receptor: a) Ion-channel linked receptors, b) G-protein couple receptors, c) Enzyme-linked receptors.

Ex: Proteins hormones and Catecholamines.

Now, we will discuss 2 mechanisms of G-protein couple receptors:

G-protein couple receptors are transmembrane proteins with 7 helical segments spanning membrane which depend on second messenger system.

First Mechanism:

Because protein can’t penetrate plasma membrane of the cell, all amino-acid-based hormones (protein hormones) exert their effects through intracellular second messengers generated by hormone binding to plasma membrane receptors.

So,

1) when the hormone (functioning as first messenger) binds to receptor found on plasma membrane, it activates catalytic subunit of G-protein to act as an intermediary to deliver the signal to adenylate cyclase to generate cAMP from ATP.

The energy for conversion of first message (hormonal) into second message (cAMP) is provided by hydrolyzing GTP into GDP.

2) Formation of cAMP activates protein kinases which phosphorylates proteins to trigger the response of target cells. Activation of protein kinases can in turn activate or inhibit some proteins.

And this mechanism is applied on Catecholamines, ACTH, FSH, LH, Glucagon, TSH, and Calcitonin.

 Most hormones need to be present for only short periods to promote the desired results so, intracellular enzyme, phosphodiesterase, is activated to degrade cAMP.

Second Mechanism:

Some hormones (such as epinephrine) act through different second messenger in other tissues:

1)     When hormone binds to receptor, it activates membrane bound Phospholipase enzyme.

2)     Phospholipase enzyme in turn splits PIP2 (Phosphatidyl inositol 4,5-biphosphate) into diacylglycerol (DAG) and IP3 (inositol triphosphate). Both of these molecules act as second messengers.

3)     DAG activate specific protein kinases whereas IP3 triggers release of Ca2+ from ER.

4)     Ca2+ acts as third messenger which either directly alter the activity of specific enzyme or plasma membrane ions or by binding to intracellular regulatory protein Calmodulin.

Notes:

1)     PIP3 (Phosphatidyl inositol 3,4,5-triphosphate) is another second messenger produced by action of phosphoinositide kinase.

2)     DAG can be generated by action of Phospholipase D that produces Phosphatide acid which is hydrolyzed into DAG.

Classification of Hormones:

Lipid-soluble hormones: they are hormones which are less soluble in water and bind to plasma protein in blood such as Vitamin D3, nitric oxide, T3, T4, Aldosterone, Testosterone, Estrogen and progesterone.

Now, the question is how these hormones work:

1)     Lipophilic hormones such as testosterone diffuses through plasma membrane of target cell and binds with receptor which is intracellularly located inside cytosol or on nucleus.

2)     Each receptor has 2 binding sites, one for hormone and other that binds to specific region of DNA (Once the hormone binds to it, hormone receptor complex binds to DNA) which is known as Hormone response element (HRE).

3)     In turn that activates the transcription of gene into mRNA.

4)     mRNA is transported out of nucleus into cytoplasm to begin translation process.

5)     mRNA binds to ribosomes to form protein or enzyme.

6)     Protein or enzyme releases from ribosome and mediates ultimate response.

The Whole process is called mobile-receptor hypothesis.

Hydrophilic hormones: they are soluble and transported in blood such as protein hormones and Catecholamines.

These hormones depend on second messenger system (G-protein coupled receptors).

Now, the question is how these hormones work:

1)     Hydrophilic hormone such as epinephrine diffuses from blood and binds to receptor found on target tissues’ surface which is plasma membrane which activates G-protein (may be stimulatory or inhibitory)

2)     Activated G-protein in turns activated adenylate cyclase which converts ATP into cAMP.

3)     cAMP activates protein kinases.

4)     Protein kinases phosphorylate one or more proteins which activate or inhibit some of them.

5)     Phosphorylated proteins which in turn cause reactions that produce physiological response.

6)     After a period, Phosphodiesterase enzyme inactivates cAMP in which cell’s response is turned off unless new hormone molecules continue to bind to their receptors in plasma membrane.

The Whole process is called Fixed-membrane receptor hypothesis.

All these processes are related to hormone signal transduction!!!!!