molecular basis

• Nervous system


  Allows us to perceive and respond to environment
• Respiratory system


  Allows us to breathe oxygen while expelling CO2
• Circulatory system


  Delivers oxygen and nutrients around our body
• Digestive system


  Enables us to extract nutrients from the food we eat
• All these physiological processes are performed and coordinated by us on a molecular level
• Cell


  Discrete little package surrounded by the plasma membrane
• Plasma membrane


  • Provides a clear boundary between outside of the cell and the inside of the cell
  • Allows the cell to regulate and control substances from entering and leaving the cell

  
• Our cells possess all the machinery and equipment that is necessary to perform all the physiological processes that are required to sustain life - single cell organisms e.g. bacteria and protozoa, multicellular organisms e.g. ourselves
• The origins of health, disease and therapeutics have a molecular basis, operational at the level of cell communication pathways
• Processes controlled and coordinated by cell communication pathways

  • Dying
  • Multiplying
  • Differentiating
  • Using energy
  • Maintaining homeostasis
• Inherited genetic mutations or infections, poor diet

  Can disrupt effective regulation of communication pathways and over time it can disrupt physiological processes
• Cell communication pathways


  Enable our cells to detect and respond to changes in internal and external environment
• Central dogma


  Describes how information in our genes is made functional - genes (DNA) are transcribed into messenger RNA which is then translated into proteins
• The signals our cell receives will determine the range of proteins that are expressed within that cell in any given time and because our proteins are structural functional machinery of our cells, the range of proteins expressed within a cell will determine that cell structure and function
• Differentiation enables groups of similar cells to work together to perform specific functions which gives rise to our tissues, then organs, then organ systems and at each of these physiological levels effective cell communication is essential to maintain the normal structure and function and regulate all biological activity and to maintain homeostasis
• Environmental factors (e.g. diet high in carbohydrate)

  Can disrupt our homeostatic mechanisms and alter the signals that our cells receive, leading to modification of their pattern of genome expression and increased risk of disease
• The molecular factors that underlie the causes and progression of diseases determine the signs and symptoms that are reported by patients, and knowledge of the molecular basis is required to reach diagnosis and treat patients safely

  
• Poor oral health has consequences for the health of our other body systems e.g. many chronic diseases can be presented with oral symptoms, likewise other oral diseases can have effect on general health
• Cell signalling pathways


  Enable cells to detect and respond to changes in their environment and coordinate their activities at the level of our tissues, organs and organ systems
• Categories of chemical signalling

  • Ligands (deliver information about the activities of one cell and communicate them to another nearby cell or even cells in distant organs)
  • Receptors (protein receptors that recognize and bind ligands)
  • Intracellular receptors (some small hydrophobic molecules can diffuse through the plasma membrane and bind to intracellular receptors)
  • Plasma membrane (framework of fat-based molecules called phospholipids - hydrophobic heads and hydrophilic tails)

  
• Cell communication


  1. Receptor ligation

  2. Signal transduction

  3. Cell response

  
• Classes of cell-surface receptors

  • G-protein coupled receptors
  • Enzyme-linked receptors
  • Ion channel receptors

  
• 1. protein coupled receptors (GPCRs)

  Largest and most diverse group of membrane receptors, interact with G-proteins (GTP), active G-proteins activate cell membrane proteins
• Enzyme-coupled receptors


  Receptor with intrinsic enzyme activity, when ligand binds to the extracellular component it causes a conformational change in the intracellular component which can then activate the enzyme

  
• Membrane receptors


  • Interact with G-proteins (GTP)
  • Active G-proteins activate cell membrane proteins
  • Up to 1000 different GPCRs
  • ~34% (475) FDA approved drugs target GPCRs (Nat Rev Drug Dis, 2017)

  
• 1. protein coupled receptors (GPCRs)


  Single protein chain, polypeptide that is folded and embedded into the cell plasma membrane, crossing the plasma membrane 7 times
• GPCR activation


  1. In absence of ligand, associated with GDP

  2. Ligand binding causes conformational change, no longer has affinity for GDP, binds GTP

  3. GTP can interact with other cell membrane proteins e.g. adenylyl cyclase
• Enzyme-coupled receptors


  • Receptor with intrinsic enzyme activity
  • When ligand binds to extracellular component, enzymatic activity on intracellular component is activated
  • Receptor Tyrosine Kinases (RTKs) largest family
  • Tyrosine kinases add PO4 to tyrosine
  • RTKs typically bind proteins at low concentrations, often involved in autocrine or paracrine signalling pathways
  • Important role in regulating cell growth, differentiation and survival

  
• Ion-channels


  • Convert chemical messages into electrical messages
  • Ligand-gated- determined by ligand binding, chemical signal
  • Voltage-gated- can measure concentration of ion within the cell
  • Important in neuronal and muscular action potentials
  • Lidocaine blocks voltage-gated Na2+

  
• Signal transduction


  1. Receptor ligation causes intracellular domain to change shape

  2. Message is delivered to inside the cell

  3. Sets off a chain of biochemical reactions (signal transduction cascades/ intracellular signalling) within the cell

  
• Second messengers


  • Small-non protein molecules
  • cAMP is a common second messenger, converted from ATP by active adenylyl cyclase
  • Hundreds of cAMP activate protein kinase A which can then phosphorylate multiple protein substrates and travel to the nucleus to activate transcription factors
• Every one receptor that is activated by its ligand hundreds of intracellular signal transduction molecules are activated

  
• These effector proteins will then affect some sort of change in the behaviour or the activity of the cell
• Cell responses


  • Regulate protein translation by turning genes on or off
  • Final target molecule may be a transcription factor – a protein that binds DNA to regulate gene transcription
• Cell signalling is hugely complex, with many signalling pathways active simultaneously, which cells must integrate, process and respond to appropriately

  
• Cell signalling pathways often converge and are integrated with each other, so a disruption of one part of the pathway can have consequences for other pathways
• Some ways cell communication pathways can be disrupted include: loss of the signal, failure to respond to a signal, failure of signal to reach target cell, over/under expression of signal, and multiple breakdowns
• Type 1 diabetes


  Autoimmune disease where the body's immune system mistakenly attacks and destroys the insulin producing cells in the pancreas
• In type 2 diabetes


  High and sustained levels of insulin are released, but cells become desensitised to insulin, so blood glucose remains high
• Receptor Tyrosine Kinase (RTK)

  When it binds to insulin, it autophosphorylates its intracellular component, but the receptor becomes desensitised, so tyrosine phosphatase dephosphorylates the receptor to keep the pathway switched off