Endocrine System: review, chemistry of hormones, gene activating methods of action (lecture 9)

• The chapter focuses on the endocrine system, reviewing hormone chemistry and outlining gene-activating methods of action.

Objectives

• Explain the differences between exocrine and endocrine glands
• Identify different endocrine organs
• Explain how endocrine glands produce and send hormones to target organs
• Determine 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

• Hormones are transported via the bloodstream to stimulate physiological responses over long distances
• Paracrine signaling involves local hormones secreted to nearby cells through diffusion over short distances; E.g., Growth factors
• Neurotransmitters transmit signals from neurons across synaptic clefts
• Contact-dependent signaling uses gap junctions, cytoplasm-to-cytoplasm connections, or membrane-bound signal molecules for cell communication. E.g., antigen presentation, where a cell displays an antigen on surface to activate immune cells
• Molecules anchored to the cell membrane interact directly receptors on adjacent surfaces
• Substances are released by neurons, diffuse across a synaptic cleft, and bind to the receptors on the surface of the next cell
• Gap junctions join unitary smooth muscle, cardiac muscle, epithelial, and other cells, enabling cells to pass nutrients, electrolytes, and signaling molecules directly from one cell's cytoplasm to the next

Glands

• Exocrine glands secrete products through ducts onto epithelial surfaces, E.g., skin, digestive tract
• Exocrine glands induce extracellular effects, E.g., digestion of food
• Mixed glands, (liver, pancreas) have both exocrine and endocrine functions
• Endocrine glands have no ducts
• Endocrine glands have a high density of capillaries, allowing for secretions into the bloodstream as internal secretions
• These capillaries are fenestrated to allow easy uptake of matter from gland tissue
• Endocrine glands bind target cells and cause intracellular effects, E.g., metabolism changes
• Skin sweat glands secrete sweat for thermoregulation
• Digestive salivary glands secrete saliva to aid digestion
• The pancreas secretes digestive enzymes
• The liver produces bile to aid in fat digestion
• Liver also secretes hormones directly into the blood
• A neuroendocrine cell is a hybrid between a neuron and an endocrine cell; E.g., adrenal medulla, hypothalamus
• Act like neurons because they receive synaptic signals from other neurons and can generate action potentials
• Act like endocrine glands because they release their secretions, such as oxytocin, into the blood

Hormone Chemistry

• Hormones have three chemical classes: steroids, monoamines, and peptides
• Steroids are made from cholesterol and include sex steroids (E.g., progesterone, testosterone) and corticosteroids (E.g., cortisol)
• Monoamines are made from amino acids; E.g., dopamine, epinephrine, norepinephrine, melatonin, and TH
• Peptides are chains of 3 to 200+ amino acids; E.g., releasing and inhibiting hormones of the hypothalamus, most pituitary hormones, and insulin

Hormone Synthesis

• Steroids differ based on functional groups added to the 4-ring steroid backbone
• Steroid production primarily occurs in ovaries, testes, and the adrenal gland via smooth ER with specific enzymes
• Monoamines are aromatic amino acids
• Tryptophan becomes melatonin
• Tyrosine requires two tyrosines to become TH
• Peptides are produced through transcription, translation (ER), folding, and modification
• Synthesis of monoamines involves decarboxylase enzymes with Vitamin B6 as a cofactor
• These enzymes are important for synthesizing monoamines like serotonin and dopamine, affecting mood and physiological functions
• Tryptophan is the precursor for melatonin production
• Tyrosine is the precursor for TH

Thyroid Hormone Production

• Enzymes add iodine to tyrosines of thyroglobulin (Tg) at the thyroid follicle
• After folding, iodinated tyrosines link to form T3 or T4 hormones
• Lysosomes hydrolyze Tg, releasing T3 + T4 hormones into the bloodstream

Gene Activation

• Steroids and TH initiate gene activation
• Steroid and thyroid hormones are hydrophobic and diffuse through the cell membrane
• Once inside, steroids + TH bind to nuclear receptors because they are hydrophobic and can pass through easily
• Target genes are activated or inactivated
• There is a time lag
• Exceptions are peptides & catecholamines because they are hydrophilic and can not easily pass through the cell membrane

Other Activation Methods

• Peptides & catecholamines use second messenger systems, (cAMP, IP3 & DAG) because some hormones are hydrophilic and cannot cross the cell membrane
• Binding to membrane, cytoplasmic, receptors triggers signaling cascades that involve second messengers
• Activate or inactivate enzymes in cells
• Rapid response is made possible by molecular switches (GTPases, protein kinases)
• They degrade faster, causing short-lived effects

IP3 & DAG

• IP3 opens calcium channels
• Ca2+ binds enzymes influencing cell metabolism
• Ca2+ binds calcium receptor in the cytoplasm, E.g., calmodulin, to activate kinases
• Ca2+ binds membrane channels, changing solute permeability and membrane potential
• DAG activates protein kinase and phosphorylates enzymes
• DAG activates or suppresses metabolism, E.g., TH release from follicular cells
• In the presence of Ca2+, calmodulin changes shape and binds to target proteins (CaM- kinases), which it then activates

Calmodulin

• Calmodulin has two globular ends connected by an α helix; each globular end has two Ca2+ binding sites
• Ca2+ binding activates calmodulin, which activates kinases
• Calcium binding changes the shape of the calmodulin protein
• Allows it to bind to a target protein (CaM-kinase), which is in turn activated
• CaM-kinases are Ca2+/calmodulin-dependent protein kinases. They are involved in learning and memory in mammalian brain
• E.g., childbirth - oxytocin binds to the receptor, which is the smooth muscle of the uterus, this causes phopholipase to release IP3. The IP3 opens channels of the sarcoplasmic reticulum, which causes the release of calcium ions into the cytosol
• Ca2+ opens Ca2+ membrane channels, which allows more Ca2+ to enter the cytosol, Ca2+ binds to calmodulin activating myosin light chain kinase (MLCK) and starts uterine contractions

Amplification of Hormone Signal

• One molecule activates many products, often enzymes
• 1 glucagon activates 1,000 cAMP molecules
• Each cAMP activates 1,000 kinases
• Each kinase activates 1,000 other enzymes
• Each enzyme activates 1,000 products
• Each glucagon yields one billion products
• Effective in small quantities, enabling impacts to body functions

Modulation of Hormones

• Up-regulation is an increased number of receptors that leads to a higher sensitivity to a hormone; E.g., in late pregnancy, uterus produces oxytocin receptors preparing for childbirth
• Down-regulation is a decreased number of receptors, reducing sensitivity to a hormone; e.g., adipocytes down-regulate in response to high concentrations of insulin. if the receptors remained at high levels, it could lead to excessive fat storage and potential insulin resistance, which is a precursor to conditions like Type II diabetes
• Down-regulation happens during long-term exposure to a hormone

Hormone Removal

• Most hormones are taken up and degraded mostly by the liver & kidneys, then excreted in bile or urine
• Others are broken down by a hormone’s target cells
• Metabolic clearance rate (MCR) is the rate of hormone removal from the blood. a higher rate indicates a shorter half-life
• Total clearance involves renal clearance + hepatic clearance + biliary clearance + other pathways
• Hormones that bind to transport proteins are removed from the blood much slower
• E.g., Growth hormone uses no transport proteins and has a half-life of only 6 to 20 minutes
• E.g., Thyroxine is protected by transport proteins and maintains a physiologically effective level in the blood for up to 2 weeks after its secretion ceases
• The equation Cls = Clr + Clh + Clb + Clother means that the total removal of the hormone from the body is the sum of its removal through the kidneys, liver, bile, and any other pathways
• The equation Cls = Dose/AUC defines clearance as the ratio of the administered dose of the hormone to the area under the curve (AUC)
• AUC is a measure of the total drug exposure over time; A higher AUC indicates longer prescence of hormones in the bloodstream. A lower AUC indicates faster removal of hormones from the bloodstream
• Inappropriate dosing with too much hormone, the drug concentrations consistently exceeds the MTC, leading to a high risk of toxicity
• The ideal dosing scenario shows a continuous IV infusion maintaining a steady state drug concentration between the Minimum Effective Concentration (MEC) and Minimum Toxic Concentration (MTC). This indicates that the dose rate perfectly matches the person's clearance (CL), ensures therapeutic efficacy with no toxicity
• Inappropriate dosing causes the drug concentration remains below the MEC, suggesting the drug may be ineffective</

This lesson reviews the endocrine system, focusing on hormone chemistry and mechanisms of action. It covers endocrine organs, hormone production, and how hormones activate cellular responses. The lesson also explores different types of hormones and signaling methods.