Introduction and MOA of Steroidal Hormones

Dr. Abhishek Roy

Junior Resident (2nd Year),

Dept. of Biochemistry,

Grant Medical College &

Sir J.J. Group of Hospitals, Mumbai

Email: mail@abhishek.roDate: 02/07/2014

Determinants of the Concentration of a Hormone at the Target Cell• The rate of synthesis and secretion of the hormones.

• The proximity of the target cell to the hormone source (dilution effect).

• The dissociation constants of the hormone with specific plasma transport proteins (if any).

• The conversion of inactive or sub-optimally active forms of the hormone into the fully active form.

• The rate of clearance from plasma by other tissues or by digestion, metabolism, or excretion.

Determinants of the Target Cell Response

• The number, relative activity, and state of occupancy of the specific receptors on the plasma membrane or in the cytoplasm or nucleus.

• The metabolism (activation or inactivation) of the hormone in the target cell.

• The presence of other factors within the cell that are necessary for the hormone response.

• Up- or down-regulation of the receptor consequent to the interaction with the ligand.

• Post-receptor de-sensitzation of the cell, including down-regulation of the receptor.

Both Recognition & Coupling Domains Occur on Receptors• The domains responsible for hormone recognition and signal

generation have been identified in the protein polypeptide and catecholamine hormone receptors.

• The dual functions of binding and coupling ultimately define a receptor, and it is the coupling of hormone binding to signal transduction—so-called receptor-effector coupling —that provides the first step in amplification of the hormonal response.

• This dual purpose also distinguishes the target cell receptor from the plasma carrier proteins that bind hormone but do not generate a signal.

Receptors Are Proteins

• The insulin receptor is a heterotetramer composed of two copies of two different protein subunits ( α2, β2 ) linked by multiple disulfide bonds in which the extracellular subunit binds insulin and the membrane-spanning subunit transduces the signal through the tyrosine protein kinase domain located in the cytoplasmic portion of this polypeptide.

• The receptors for insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) are generally similar in structure to the insulin receptor.

• A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains.

General features of Hormone Classes

Group I

• Types Steroids, Iodothyronines,

Calcitriols, retinoids

• Solubility Lipophilic

• Transport proteins Yes

• Plasma half-life Long(Hours to days)

• Receptor Intracellular

• Mediator Receptor-Hormone Complex

Group II

Polypeptides,Glycoproteins

Catecholamines, Proteins

Hydrophilic

No

Short (Minutes)

Plasma Membrane

cAMP, cGMP, Ca2+ etc.

Hormones that bind to intracellular receptors

• Calcitriol

• Glucocorticoids

• Mineralocorticoids

• Progestins

• Retinoic Acids

• Thyroid Hormones (T3 and T4)

Hormones that bind to cell surface receptors

• Second messenger is c-AMP α2 and β Adrenergic Catecholamines

ACTH

ADH

Calcitonin

FSH

CRH

LH

PTH

TSH

Somatostatin

Glucagon

• The Second Messenger is c-GMPANF

NO

• The second Messenger is Ca2+ or Phosphatidylinositol (or Both)α1 Adrenergic catecholamines

Cholecystokinin

Gastrin

Oxytocin

TRH

PDGF

Angiotensin-II

• The second messenger is a kinase or phosphatase cascade• Adiponectin

• Chorionic somato-mammotropin

• Epidermal growth factor

• Erythropoietin

• Fibroblast growth factor (FGF)

• Growth hormone (GH)

• Insulin

• Insulin-like growth factors I and II

• Leptin

• Nerve growth factor (NGF)

• Platelet-derived growth factor

• Prolactin

The DNA Sequences of Several Hormone Response Elements (HREs)

• Glucocorticoids GRE GGTACA NNN TGTTCT

• Progestins PRE

• Mineralocorticoids MRE

• Androgens ARE

• Estrogens ERE AGGTCA NNN TGA/TCCT

• Thyroid hormone TRE

• Retinoic acid RARE AGGTCA N3,4,5 AGGTCA

• Vitamin D VDRE

• cAMP CRE TGACGTCA