Homeostasis and Control Systems

• Homeostasis is the concept of constancy and a central theme for bodily function.
• Disturbance in homeostasis leads to disease.
• Claude Bernard coined the term "milieu interieur" (internal environment).
• Walter Cannon coined the term "homeostasis."

Control Systems of Homeostasis

• Mechanisms the body uses to maintain homeostasis.
• These mechanisms include negative feedback, positive feedback, and feedforward systems.

Negative Feedback

• Negative feedback occurs when an increase in a stimulus leads to a decrease in parameters.
• Example: Baroreflex which regulates changes in blood pressure.
• Blood pressure increases during exercise and decreases after exercise.
• Endocrine hormone regulation accounts for 99% of hormonal control.
• Gastric acid secretion is also regulated by negative feedback.

Components of Negative Feedback

• Stimulus: Blood Pressure (BP)
• Acts on receptors called baroreceptors.
• Afferents: Transmit signals to the center.
• Centre: Medulla
• Efferents:
• Sympathetic Nervous System (SNS) increases heart rate (HR) and BP.
• Parasympathetic Nervous System (PNS) decreases HR and BP.
• Response: Change in Blood Pressure (BP).

Assessment of Effectiveness of Negative Feedback

• Gain (G) = Correction by the System (C) / Error remaining (E)

Infinite Feedback Gain

• Occurs when the error becomes zero, resulting in infinite gain.
• Kidneys always correct blood pressure back to normal.
• In hypertension (HTN), if kidneys are affected, blood pressure never returns to normal.

Positive Feedback

• An increase in the initiating stimulus leads to a further increase in response.
• Amplifies reactions, also known as a vicious cycle and destabilizes the system.
• Example: CLAPS (mnemonic) including:
• Coagulation cascade.
• LH surge: Only exception for true feedback in endocrine hormone regulation.
• Action potential.
• Parturition (Normal delivery) referred to as Ferguson reflex.

Feedforward Control System

• Core theme: Anticipatory control system, where the body responds anticipating a stimulus.
• Example: Anticipatory tachycardia and tachypnea which are the increased respiratory rate (IRR) and increased heart rate (HR) before exercise.
• Anticipatory motor control involves the cerebellum.
• Person driving on a highway applies the brakes on seeing a cow (anticipates danger).
• Anticipatory regulation of core body temperature:
• Skin temperature affects shell temperature.
• Body organ temperature affects core temperature.
• In a cold environment, the shell temperature decreases. Hypothalamus anticipates a decrease in core temperature and initiates corrective measures to maintain core temperature.

Properties of Homeostasis

• Dynamic Constancy: AKA dynamic equilibrium.
• Homeostatic control systems maintain a "range of values".
• Normal heart rate (HR) is 60-100 bpm.
• Normal respiratory rate (RR) is 12-18 bpm.

Prioritization of Parameters for Correction

• pH > Blood Pressure (BP) > Temperature
• pH changes are given more priority as they affect enzyme activity, leading to death if not corrected.

Cell Membrane

• AKA plasma membrane.
• Function: Outer barrier with selective permeability.
• Structure: Described by the Fluid Mosaic Model, proposed by Singer and Nicolson.
• Composition:
• Proteins (55%): Arranged in a mosaic pattern.
• Lipids (40%): Responsible for fluidity.
• Carbohydrates (5%).

Lipids

• Introduction:
• Bilayer: Outer and inner lipids.
• Asymmetry: Arranged specifically on either inner or outer side.
• Types:
• Phospholipids (PO4 group).
• Glycolipids (Carbohydrate side chain).
• Cholesterol (Critical lipid).
• Phospholipids: Major lipid.

Phospholipids

• Phosphatidylcholine (PC) / Lecithin:
• Site: Lungs (surfactant).
• Significance: Prevents alveolar collapse is a major lipid in surfactant.
• Sphingomyelin:
• Site: Nerve cell membrane / Surfactant.
• Significance: Minor lipid in surfactant.
• Phosphatidylinositol (IP3):
• Site: Endocrine cells.
• Significance: Part of second messenger system (IP3 → DAG → Ca++).
• Phosphatidylserine (PS):
• Site: Inner surface of cell membrane in all cells. If expressed on the outer surface, it signals "Eat me"
• Significance: Signals Apoptosis (Programmed cell death) and is detected by Annexin V. Binds & forms a complex with PS (Annexin V staining).
• In syphilis: Serum anti-CL antibody + (Detected by VDRL test)
• Cardiolipin (CL):
• Site: Heart (mitochondria).
• Note:
• L (Lecithin) / S (Sphingomyelin) ratio is used to assess fetal lung maturity.
• Mature lung: ≥ 2.

Glycolipids

• Types:
• Cerebrosides: Site is CNS.
• Gangliosides: Site is GIT, GM-1 gangliosides are receptors for cholera toxin-Fragment B.

Cholesterol

• Site: Cell membrane of skin.
• Significance:
• Precursor of Vitamin D.
• 7-dehydrocholesterol converts to Vitamin D via sunlight (skin).
• Fluidity buffer which maintains membrane fluidity in optimal range.

Membrane Fluidity

• Lubricative property of lipid maintains fluidity of membrane and allows mobility.
• Characteristics of Fluidity:
• Increased Fluidity (Good):
• Unsaturated (Essential) fatty acids like Linoleic acid, Linolenic acid, Arachidonic acid and Omega-3 fatty acids (abundant in fish).
• Decreased Fluidity (Bad):
• Saturated (Trans) fatty acids like Stearic acid and Palmitic acid (abundant in junk food).

Proteins

Classification based on location in cell membrane

• Transmembrane/Integral: Present throughout.
• Peripheral: Present peripherally.
• Lipid-anchored: Requires lipids for attachment.

Transmembrane Proteins

• Most important.
• Functions:
  • Hormone receptors (most common): Example is GPCR (G-protein coupled receptors)
  • Pump channels: Example is Na+-K+ ATPase.
  • Ion channels:
    • Cl- channel (CFTR).
    • (Cystic Fibrosis Transmembrane Conductance Regulator.)
    • In cystic Fibrosis CFTR mutation (+).

Peripheral Proteins

• Functions:
  • Support shape of cell.

Diseases due to Mutations

• RBC (Biconcave disc): Protein is Spectrin and the disease is Elliptocytosis
• RBC (Biconcave disc): Protein is Ankyrin and the disease is Spherocytosis
• Skeletal Muscle: Protein is Dystrophin and the diseases are:
  • Duchenne Muscular Dystrophy (DMD): Muscular weakness, a typical presentation.
  • Gower's sign: climb on own body to stand up (Knee → Hip → Stand).
  • Respiratory paralysis (weakness of diaphragm) leading to Death

Lipid Anchored Proteins

• In RBC:
• PIGA (Phosphatidylinositol Glycan-A) gene synthesizes proteins.
• CD55 (Decay accelerating factor).
• CD59 (Membrane inhibitor of reactive lysis).
• C8 binding protein.
• Proteins bind to lipid: Phosphatidylinositol.
• Significance:
• Normal gene: Prevent hemolysis.
• Mutated gene: Paroxysmal Nocturnal Hemoglobinuria which is mutated or absent PIGA gene
• During sleep (night) the PH and activates complement proteins: C5-C9 activating membrane attack complex, which attacks RBC membrane leading to Hemolysis (Hemoglobinuria).

Treatment

• Anti C5 monoclonal antibody: Supportive.
  • Eculizumab.
  • Ravulizumab (Long acting).
• Hematopoietic stem cell transplant: Definitive.

Carbohydrates

• Classifications:
• Glycoprotein: Attached to proteins.
• Glycolipids: Attached to lipids.
• Significance: Glycolipids on RBC membrane determine blood groups.
• Note:
  • Membrane with highest protein content: inner mitochondrial membrane.
  • In nerve cell membrane (Myelin): Lipid (80%): Protein (20%).
  • Repair of damaged cell membrane is by resealing of lipid bilayer.
  • Deficiency of lecithin in pre-term baby: Hyaline Membrane Disease.

Cell Organelles

• Endoplasmic Reticulum: Types:
• Rough Endoplasmic Reticulum (RER): Has a granular surface d/t presence of ribosomes, AKA granular ER. Smooth Endoplasmic Reticulum (SER): Has a smooth surface d/t absence of ribosomes, AKA agranular ER.

ROUGH ENDOPLASMIC RETICULUM:

• Functions:
• Protein synthesis/translation.
• Folding of proteins: Using chaperones/heat shock proteins (HSP).
• Degradation of misfolded proteins & quality control of proteins by unfolded protein response or ER stress response.
• ↑↑Misfolded proteins lead to ER stress.
  • Halts protein synthesis.
  • Endoplasmic reticulum-associated degradation (ERAD) is activated.
• ERAD:
  • Misfolded proteins are tagged to ubiquitin (kiss of death). Protein-ubiquitin complex moves to proteasome (Graveyard of the cell) and undergoes degradation.
• Applied aspect
  • Misfolded protein diseases:
    • Alzheimer's disease: more common due to accumulation of misfolded AB amyloid protein.
    • Prion disease: PrPc (Normal protein in CNS) PrPsc (Prion protein: misfolded).
    • Eg: Creutzfeldt Jakob disease (very fatal).

SMOOTH ENDOPLASMIC RETICULUM:

• Functions:
• Synthesis of Steroid hormones: Adrenal cortex (Aldosterone, Cortisol), Testis (Testosterone), Ovary (Estrogen).
• Storage of Ca2+: SER of skeletal muscle stores Ca2+ (sarcoplasmic reticulum).
• Drug detoxification (xenobiosis): Major site is Liver SER.
• Enzyme is Cytochrome P450 (CYP450).

Golgi Apparatus

• Location: Close to RER
• Functions:
• Post-translational modifications: Proteins synthesized by RER ends at
• Cis end of Golgi apparatus (GA)
• Glycosylation (Carbohydrate side chain added to the protein) produces
• Glycoprotein (Stability of protein) which is stored in vesicles with stimulation.
• Released from trans end where GA are abundant in secretory cells.
• Antibody secreting plasma cells, Goblet cells of GI tract is sorted into a GA molecule.

Sorting of proteins:

• GA determines where a protein is delivered.
• Protein + Phosphotransferase → Protein + mannose-6-phosphate which moves to lysosome and degrades.

I cell disease

• Absence of phosphotransferase mannose-6-phosphate is not added
• Lysosomal function affected, proteins not degraded Inclusion bodies accumulate in the cell..

Lysosomes

• Recycle bin of the cell.
• Functions:
• Acid mediated destruction, by the means of enzymes, such as H'ATPase acid hydrolase and Acid hydroxylase enzyme.

Autophagy:

• Destruction of the cell's own part, late stages.
• Lysosomes engulf mitochondria, proteins released from mitochondria undergo metabolism, leading to Energy for Survival.
• Clinical Application:
• Neutrophil has a High content of lysosomes.
• CHSI Normal → LYST (Lysosomal transport Protein) Mutation Chediak Higashi Syndrome; therefore patient is bacterial infection prone.

Peroxisomes

• Rich in proteins
• Function: oxidation of very long chain fatty acids (VLCFAS): generates H2O2 (free radical).
• Degradation of H2O2: catalase, pseudocatalase is useful for commercial drug: treats free medication disorders.
• Enzymes for peroxisomes includes plasmarogens (mylen sheath) and luciferase (glow fires/ glow in fireflies). Peroxisomal Storage Disorders:
• zellweger syndrome a. pex mutation: b. PEX codes for proteins (proteins for peroxisome synthesis) -Features: a. accumulation of VLCFA's. b. plasmagens neurological impairment -Refums disease - PAHX mutation -Defective in phytonyl, defective oxidation of prythanic acid.

Adrenoleukodystrophy Defect

• Defect in transfer proteins VLCFA increases (neurological impairment).

Mitochondria

• Intermembranous space Inner membrane has crista (oxidative phosphorylation ATP synthesis). Powerhouse of cell Mitochondrial: Has its own DNA DNA theory, sourced by Ovum inheritance for ds DNA of base of pairs Repair of mutations mitochondrial DNA: ineffective. Mitochondrial: disorders organs with high metabolic requirements: Affect skeletal muscles, stroke like function, GI tract. MELAS- Encephalopathy (Affects organs with high metabolic requirements: Features: contraction relaxation.↑Suspect infection Lactic Acidosis, CNS stroke symptoms.

Nucleus: Contains RNAs and ribosomes, contains chromosome

• DNA histones chromatin.
• Structural unit for chromosomes -Nucleosomas Regulated nuclear complex entry and exit to the nucleus Exports/ imports moving with subsides of proteins

Marker Enzymes:

• Help identify cells in an organelle.

Cytoskeletal Filaments and Cellular Junctions

• Cytoskeletal Filaments have cell body or bone which help:
  • Cell strength has 3 types:
  • Microfilm: micro filaments
  • Tubes cell membrane: intracellular filaments with protein. Function: Axon transport with terminal transport and body synapse

Proteins: kinesin:

• Speed of transport: Fast (400mm) vs slow
• Clinal significance transports in micro organism rabies vs tetanus
• Cillany motility- Clearing sputum vs embryological development rotation of internal organs. -9=2 micro tubular are angement+dyenin arm= cilia movement. -Clinical significane- immbile syndrome + bronchieactasis
• Sperm +cell mobility
• Chromsomal Movemnt- Tubulin+signigance movmeents of hromomes.
• Drugs vs anti gout colchicne.
• Micro Filament -actin, micro filaments skeletal musccel, micro tubles- Sliding filament theory Clinical- Internal Listeria and Invale cells - skin disorders Desmoglein and autoimmune desmglkin and skin tensionfillins.