Lecture 9: Hormone Chemistry and Gene Activation

• Endocrine System is the main topic, specifically, the chemistry of hormones and gene activating methods of action will be reviewed.

Objectives

• Describe the differences between exocrine and endocrine glands.
• Describe the different endocrine organs.
• Explain how endocrine glands produce and send hormones to target organs.
• Describe the main types of hormones.
• Describe how hormones are synthesized.
• Describe how hormones activate cellular responses.
• Describe how hormone signaling is regulated.

Communication in the body

• Cells communicate with each other.
• Hormones are transported by the bloodstream and stimulate physiological responses over a long distance.
• Paracrine signals involve cells secreting "local hormones" to nearby cells through diffusion over a short distance, exemplified by growth factors.
• Neurotransmitters transmit signals from neurons across a synaptic cleft.
• Contact-dependent signaling involves gap junctions, interactions from cytoplasm to cytoplasm, and membrane-bound signal molecules for antigen presentation.

Exocrine Glands

• Secrete products through ducts onto epithelial surfaces.
• Skin and the digestive tract are examples.
• Have extracellular effects like digestion of food.
• Liver and pancreas are examples of mixed glands.

Endocrine Glands

• Don't have ducts
• Have a high density of capillaries that are fenestrated.
• Release secretions into the bloodstream.
• "Internal secretions"
• Bind target cells, causing intracellular effects like altering metabolism.

Neuroendocrine cells

• Hybrid between a neuron and an endocrine cell.
• Adrenal medulla and hypothalamus are examples.
• Neuroendocrine cells receive synaptic signals from other neurons and produce action potentials, secreting hormones into the bloodstream.

Endocrine System

• Glands, tissues, and cells secrete hormones.

Hormone Chemistry

• Hormones can be divided into three chemical classes: steroid, monoamines, and peptides.
• Steroids are made from cholesterol.
• Progesterone and testosterone are examples of sex steroids.
• Cortisol is a corticosteroid.
• Monoamines are made from amino acids.
• Dopamine, epinephrine, norepinephrine, melatonin, and TH are examples of monoamines.
• Peptides consist of 3 to 200+ amino acids.
• Hypothalamus-releasing and inhibiting hormones, most pituitary hormones, and insulin are examples of peptides.

Hormone Synthesis

• Steroids differ based on functional groups added to the steroid backbone which has 4 rings.
• Steroid hormones are produced in the ovaries, testes, and adrenal gland.
• Steroid production occurs in the smooth ER using enzymes.
• Monoamines are synthesized from aromatic amino acids using decarboxylase enzymes, which requires Vitamin B6
• Tryptophan is converted to melatonin, and Tyrosine is converted to TH, and has 2 tyrosines.
• Peptides are produced like other proteins, through transcription and translation (ER), followed by folding and modification.

Thyroid Hormone Production

• An enzyme adds iodine to tyrosines of thyroglobulin (Tg).
• Thyroglobulin folds and the tyrosines link together.
• Lysosomes hydrolyze thyroglobulin.
• TSH

Gene Activation

• Steroids and thyroid hormones (TH) are hydrophobic and diffuse through the membrane.
• Once inside of the cell, the steroid or TH binds to a nuclear or cytoplasmic receptor, where it can target particular genes causing their activation or inactivation over a period of time.
• Glucocorticoids are an example.

A Coordinated Unit

• Genes with hepatic expression levels are correlated with cortisol concentration.

Other Activation Methods

• Peptides and catecholamines make use of second messenger systems.
• ATP converts to cAMP.
• PIP2 converts to IP3 & DAG.
• Enzymes are activated or inactivated in cells.
• Characterized as rapid responses, often employing molecular switches like GTPases and protein kinases.
• These processes are degraded faster and have short-lived effects.

IP3 & DAG

• IP3 opens calcium channels.
• Calcium ions then bind to enzymes, resulting in cell metabolism.
• Calcium ions bind calcium receptor in cytoplasm, for example, Calmodulin, and activate kinases
• Calcium ions bind membrane channels to change solute permeability and alter membrane potential.
• DAG activates protein kinase; it phosphorylates enzymes, activates or suppresses metabolism, and has a role with thyrotropin releasing hormone (TH) release from follicular cells.

Calmodulin Structure

• Has two globular ends connected by a long α helix.
• Each globular end has two Ca²⁺-binding sites.
• Ca²⁺ binding activates calmodulin and activates kinases.

Amplification of Hormone Signal

• One hormone molecule triggers many products via enzymes
• 1 glucagon 1,000 cAMP molecules.
• Each cAMP → 1,000 kinases
• Each kinase → 1000 other enzymes
• Each enzyme 1000 products
• A single glucagon results in 1 billion product.
• Hormones are effective in small quantities.

Modulation of Hormones

• Upregulation involves an increase in the number of receptors, which makes the cell more sensitive to the hormone.
• Downregulation involves a decrease in the number of receptors, which lowers the cell's sensitivity to the hormone during long-term exposure.

Hormone Removal

• Breakdown occurs mostly in the liver and kidneys.
• It also happens in the hormone's target cells.
• The metabolic clearance rate (MCR) is the rate of hormone removal from the blood.
• A higher rate will lead to a shorter half-life.
• ClS = CIr+ClH+ClB+Clother
• Cl₃ = Dose/AUC.

Cls & Clinical Pharmacokinetics

• Ideal therapy is efficacy without toxicity.
• Continuous IV infusion at a steady rate in which the dose-rate is exactly appropriate for the patient's clearance.
• Inappropriate dosing may be either too high, resulting in toxicity, or too low, making the drug ineffective.

Childbirth example

• Oxytocin binds to receptors on the smooth muscle of the uterus.
• Phospholipase releases IP3, which opens channels of the sarcoplasmic reticulum, causing Ca2+ to enter the cytosol.
• Calcium ions open more calcium channels in the membrane, increasing cytosolic Ca2+.
• Calcium ions bind to calmodulin, which activates myosin light chain kinase (MLCK) and leads to uterine contractions.
• Calmodulin is the functional equivalent of (similar to) troponin in smooth muscle cells

Signal Amplification additional information.

• Epinephrine interacts with a plasma membrane receptor leading to a cascade of events and an eventual 10^8 increase of glucose-1-phosphate

Next steps

• Modes of secretion, hypothalamic-pituitary control.