Nervous and Musculoskeletal systems

• Bone can be broken into two regions:

  • Cortical bone: high density, external layer, low porousness, compact with osteons surrounded by concentric lamellae. Provides strength to structure
  • Cancellous bone (trabecular / spongy): low bone density, network of thin porous trabeculae in directions of stress, large SA for mineral exchange (Ca - 99%, Phosphate - 85%), maintains skeletal strength and integrity
• The bone matrix composes of:

  • Collagen I: provides elasticity
  • Hydroxyapatite crystals: provides rigidity

  If:

  • Too much hydroxyapatite: brittle bonds
  • Too much collagen: bendy bones

  Thus, mineral contents need to be in homeostasis.
• Bone remodelling is the turnover of new bone matrix. This is needed to:

  • Obtain optimal shape in response to load
  • Repair damages (micro and macro tears)
  • Prevent accumulation of aged tissue
  • Supply calcium and phosphate into bloodstream
• Cells involved in bone remodelling:

  • Osteoclasts: facilitate bone resorption through secreting acids (demineralisation) and proteases which breaks down collagen I (CTX - serum marker for bone resorption). Allows for liberation of calcium and phosphate into circulation. Is derived from haematopoietic precursor cells and are multinucleated.
• Cells involved in bone remodelling:

  • Osteoblasts: facilitate bone formation by forming osteoids and then mineralising them. Forms collagen I by breaking down pro-collagen (P1NP is released which is a serum marker for bone formation). Is derived from mesenchymal lineage
• Cells involved in bone remodelling:

  • Osteocytes: mechanosensing cells. Terminally differentiated osteoblasts embedded in within bone, forming a canalicular network between each other. Releases factors increasing RANKL, binds to receptors on osteoclast precursors to stimulate osteoclast formation, factors which increase osteocyte activity and factors which decrease osteoblast activity
• Calcitriol (active vitamin D3) is active after vitamin D3 becomes absorbed through the skin and travels through the liver and kidneys.

  The secretion of parathyroid hormone is stimulated when calcium levels are low.
• Calcitriol regulates serum Ca2+ by:

  • Increasing calcium intestinal absorption
  • Increasing calcium renal reabsorption
  • Increasing parathyroid hormone production (indirectly)
  • Increasing bone resorption and decreasing bone formation to release Ca2+ into circulation

  Calcitriol is inhibited by high levels of calcium and phosphate.

  Parathyroid hormone similarly regulates Ca2+ by:

  • increasing bone resorption
  • Reducing excretion in kidneys (conserve calcium)
  • stimulate calcitriol production

  Parathyroid hormone is a short-term regulator whereas calcitriol is a long-term regulator
• Glial cells in the nervous system:

  In the CNS:

  • Ependymal cells (creates barriers between compartments and source of neural stem cells)
  • Astrocytes (source of neural stem cells, take up neurotransmitters, secrete neurotrophic factors, help form blood-brain barrier and provides substrates for ATP production)
  • Microglia (modified immune cells that act as scavengers)
  • Oligodendrocytes (forms myelin sheaths)

  IN PNS:

  • Schwann cells (forms myelin sheaths and secretes neurotrophic factors)
  • Satellite cells (supports cell bodies)
• In the intracellular fluid, there is a high conc. of K+ and low conc. of Na+.

  In the extracellular fluid, there is a low conc. of K+ and a high conc. of Na+.
• Permeability refers to the ability of an ion to move through the cell membrane.

  In the nervous system:

  • A higher K+ permeability means that more K+ ions move from the intracellular fluid to the extracellular fluid, making membrane potential more negative
  • A higher Na+ permeability means that more Na+ ions move from the extracellular fluid to the intracellular fluid, making the membrane potential more positive
• Ions move through the cell membrane through channels:

  • Leak channels are always open
  • Potassium sodium ion pump (active - maintains membrane potential at -70 mV)
  • Voltage-gated ion channels (dependent on voltage)
  • Ligand-gated ion channels (either intracellular or extracellular ligands)
  • Stress-activated channel (e.g. touch sensations)
• Graded potentials are local in site, and are produced by any stimulus that can open a gated channel. They can be either depolarisation (more positive via Na+ entering) or hyperpolarisation (more negative via K+ exit).

  Amplitude of grade potential is inversely proportional to distance from stimulus. If the amplitude at trigger zone (axon hillock) is above the threshold, then an action potential will be generated
• Graded potentials that are sub-threshold have the ability to become threshold through:

  • Temporal summation: potentials occur at the same location but close in timing
  • Spatial summation: potentials occur at the same time but close in location
• The threshold voltage is between -60 to -55 mV and if the amplitude of the graded potential is large enough to exceed this, an action potential will be generated (all are identical and independent of strength of stimulus)
• Stages of the action potential:

  • Depolarisation: membrane potential becomes more positive due to the opening of voltage-dependent Na+ channels (activation gate opens), causing Na+ to move into the cell
  • Repolarisation: membrane potential starts decreasing once Na+ channels close (inactivation gate closes) and slow voltage-gated K+ channels open, causing K+ to move out of the cell
  • Hyperpolarisation: K+ channels close once membrane potential is lower than that of resting potential
  • Voltage increases back to -70 mV and permeability returns to normal
• Na+ entering into the cell is a positive feedback loop. However, the closing of the inactivation gate in the voltage-gated Na+ channels prevents back flow of membrane potential. This is called an absolute refractory period where all Na+ channels are either open or inactivated.

  
  

  On the other hand, relative refractory period, occurring after its absolute counterpart, occurs when Na+ channels begin to resume into resting state, allowing an action potential to fire but requiring a larger than normal stimulus
• Myelin is a membraneous wrapping of insulation around axons. This is to increase the conduction velocity of the action potential by decreasing resistance, decreasing current leaking out of axons. Thus, ion channels are only required at nodes of ranvier
• Continuous propagation occurs for unmyelinated axons whereas saltatory propagation occurs for myelinated axons
• Conduction velocity increases with:

  • an increase in myelination
  • an increase in axon diameter (less leakage)
  • an increase in temperature
• Three types of nervous fibres:

  • Type A (highest conductive velocity): myelinated and large axon diameter
  • Type B (second highest): myelinated but small axon diameter
  • Type C (lowest): unmyelinated and small axon diameter
• A synapse is a junction between a neuron and another cell (neuron or effector cell)
• Synapses can either be:

  Electrical: presynaptic and postsynaptic cells are locked together and APs are bidirectional

  Chemical: Uses neurotransmitters to propagate AP into postsynaptic cell
• A neurotransmitter can either be:

  • excitatory: causes depolarisation event
  • Inhibitory: causes hyperpolarisation event

  Misleading classification due to receptor dependence -> structural classes preferred instead
• Neurotransmitters are synthesised either at:

  • synaptic terminals: for small neurotransmitters
  • Cell body: for peptide neurotransmitters
• Mechanism of neurotransmitter release:

  • AP that is propagated by threshold graded potential reaching axon hillock causes depolarisation on presynaptic axon terminal
  • voltage gated calcium channels open and cause calcium to enter cell
  • Calcium causes exocytosis of neurotransmitters to occur, where docking proteins come into contact with cell membrane
  • neurotransmitter is released into synaptic cleft and binds to receptors on postsynaptic cell
  • response is delivered
• The stimulus strength is proportional to the frequency of APs propagated
• Two receptor types:

  Ligand gated ion channels (ionotropic): directly impact ion permeability

  G protein coupled receptor (metabotropic): ion channel opening relies on intermediary second messenger
• Neurotransmitters can be terminated via:

  • active transport back into presynaptic cell or glial cell
  • Enzymic breakdown (e.g. acytalcholinesterase turns acetylcholine into acetate and choline)
  • neurotransmitter diffuses out of cleft into blood vessels
• Neuromuscular junction (NMJ): The synapse between the alpha neuron and skeletal muscle fibres. The motor end plate is the region of muscle membrane that contains a high concentration of acetylcholine receptors
• The nicotinic receptors on NMJ are non-selective cation channels and both Na+ and K+ movement is due to chemical gradients (sodium is due to electrical too)
• Acetylcholine is synthesised in axon terminal when chlorine, produced when acetylcholinesterase catalyses acetylcholine into acetate and choline, reacts with acetyl-CoA, produced when CoA enters mitochondria
• Post synaptic events:

  • AP is propagated into t-tubule
  • The conformation of Dihydropyridine (DHP) L-type calcium channel is altered
  • This causes ryanodine receptor channel to open, releasing calcium ions from the sarcoplasmic reticulum
  • Calcium binds to troponin, allowing actin-myosin binding, causing myosin to execute power stroke and cause actin filament to move towards centre of sarcomere