Introductory Physiology PDF

Introductory Physiology Physiology is the science of functional activities and related mechanisms in the body Physis is Nature in Greek, and Logos means study  William Harvey in 17nth century described the circulatory system. In Chapter 13, Harvey summarized the...

Introductory Physiology Physiology is the science of functional activities and related mechanisms in the body Physis is Nature in Greek, and Logos means study  William Harvey in 17nth century described the circulatory system. In Chapter 13, Harvey summarized the substance of his findings: "It has been shown by reason and experiment that blood by the beat of the ventricles flows through the lungs and heart and is pumped to the whole body. There it passes through pores in the flesh into the veins through which it returns from the periphery everywhere to the centre, from the smaller veins into the larger ones, finally coming to the vena cava and right atrium. This occurs in such an amount, with such an outflow through the arteries and such a reflux through the veins, that it cannot be supplied by the food consumed. It is also much more than is needed for nutrition. It must therefore be concluded that the blood in the animal body moves around in a circle continuously and that the action or function of the heart is to accomplish this by pumping. This is only reason for the motion and beat of the heart."  Claude Bernard established physiology as the scientific basis of medicine His main contribution to physiology and medicine is probably the creation of the concept of «milieu intérieur» and its constancy, which was later called homeostasis. Claude Bernard wrote “For the animal there are really two environments: an external environment in which the organism is placed, and an internal environment in which the elements of the tissue live…. The fixity of the internal environment is the condition of free and independent life” Human Physiology is the science of physiological functions in human body Carnegie Stage: Based on the maturity of the embryo Sketch of the primitive cardiovascular system in an embryo of about 26 days, (Moore and Persaud, 1998). Development of Blood Vessels and Fetal Circulation | Anatomy and Physiology II Positive Feedback Mechanisms in Physiology Negative Feedback Mechanisms in Physiology Tissues with functions Cellular Organization of brain Subarachnoid space containing the CSF Basal lamina Subpial astrocytes Neurons and glia Subependymal astrocytes Ciliated ependymal cells Ventricle Organization of brain: Cerebrospinal fluid Goverman etal., 2009 General structure of neurons Includes Perikarya, Dendrites and Axons Classification of Neurons  How Complexity of CNS is generated 1. The mechanisms by which neurons produce signals 2. The pattern of connection between cells 3. The relation ship of different patterns of interconnection to different types of behavior 4. The means by which neurons and their connections are modified by experience. The functional unit of a neuron Adopted from Salzer group Kim and Pfeiffer 1999 Salzer Neuron 2003  A schematic representation of multilamellar myelin and myelin-axolemmal organization at nodes of ranvier Longitudinal section of a myelinated nerve at paranode Kv 1.2 Caspr-1 Na Ch. Transverse section of a Axon myelinated nerve Multilamellar myelin Rasband et al., 2001 Extracellular phase Intracellular Cytoplasmic Phase MBP (Myelin Basic Protein) MBP plays a key role in keeping the multilamellar myelin together Ultrastructure and molecular organization of nodes The insulating myelin sheath of the axon has regularly spaced gaps called the nodes of Ranvier. Electron micrographs show the region of nodes in axons from the peripheral nervous system, spinal cord, and cerebral cortex. The axon (Ax) runs from the top to the bottom in all three micrographs. The axon is coated with many layers of myelin (M), which is lacking at the nodes (Nd), where the axolemma (Al) is exposed. (In the Kv 1.2 Caspr-1 Na Ch. peripheral nervous system the support cell responsible for myelination is called a Schwann cell (Sc), and the central nervous system it is an oligodendrocyte.) The elements of the cytoskeleton that can be seen within the axon are microtubules (Mt) and neurofilaments (Nf). Mitochondria (Mit) are also seen. (From Peters et al. 1991.) Rasband et al., 2001  Functions of Neurons Effects Functionality Excitatory Motor Inhibitory Sensory Modulatory Secretory  Myelin Disorganizations in Diseases Facilitates the conduction of impulses across the axons Organizes the nodes of ranvier In Multiple Sclerosis both myelin and the underlying axon is damaged Axon Demyelinated Area (plaques) White matter Courtesy Medlib, Utah MS brain Localization and clustering of Node, Paranode and Juxtaparanode molecules in WT and CGT(Ceramide Galactosyl Transferase) CGT null animals showed a disorganized distribution of node, paranode, juxtaparanode molecules.  Polarity Neurons sprout into neurites These neurites guide them to its resting position Acquire either axonal or dendritic identity Commitment phase (growth promoting molecules become restricted to one neurite only, the future axon) Changes a neuron from a motile cell, with actively extending and retracting neurites into a stationary cell and the unique axon steadily grows towards its target. Neurons sense the environment at growth cones  Polarity Growth cones transduce signals to the cytoskeleton, mitochondria and membrane reservoirs Restriction of the protease activity of calpain to the neurite shaft in developing neurons is a key event in the stabilization of these extensions  Changes in neuronal morphology during neuronal polarization The arrowheads indicate the axon. Red staining represents actin filaments, whereas microtubules are shown by green staining. The blue staining in (d) shows synapsin 1, which concentrates at the presynaptic terminal.  Elements of the cytoskeleton Microtubules Intermediate Actin filaments filaments Neuronal polarity-regulating molecules Model of positive and negative signals  Transport of key regulators in axon formation by kinesin Kinesins - microtubule plus-end-directed motor WAVE - Regulates actin filament stability during lamellipodia formation CRMP2 - promote neurite elongation and axon specification by regulating microtubule assembly, endocytosis of adhesion molecules and reorganization of actin filaments Introductory Physiology Electrical properties, Action Potential and Impulse Conduction along a Neuron A depolarization wave A depolarization wave and the ion channels responsible  Passive electrical properties of a neuron Resting membrane resistance Membrane capacitance Intracellular axial resistance along axons and dendrites Larger the diameter, lower the axial resistance V = Q/C or C =Q/V Q = charge C = Capacitance  The plates are the saline solution each side of the membrane And The membrane is the insulator separating the plates Speed of depolarization is slowed down by the time it takes to discharge the membrane capacitance Therefore the action potential can die back. Thus, capacitance has to reduce by: Increasing the diameter of axon Or reduce the capacitance by moving the plates farther by myelination  Resting membrane potential During resting membrane potential K+ diffuses out & Na + moves into the cell via: Chemical driving force Electrical driving force The two driving forces are determined by concentration gradients and the electrical potential difference As a result K+ diffuses out and Na + moves in However, Na+/K+ pump moves Na+ and K+ against their chemical gradients Resting potential is maintained by three main players 1. Na+ channels inward Na+ movement 2. K+ Channels outward K+ movement 3. Na/K pump (ATP dependent) 3Na+ ions taken out and 2K+ ions are brought in (Na/K pump’s job is to make sure that more positive ions remain outside the cell) As a result, Na+ ions are concentrated outside and K+ ions are concentrated inside the cell  During the initiation stages of an action potential: K+ channels close and Na+ ions moves in through Na+ channel and depolarization happens by becoming positive inside Now Na+ channels closes and K+ moves out through K+ channel Next Na/K pump brings the membrane potential to resting status Anatomy of action potential How is this possible ?  Ion channels Conduct ions ≈ 100 million/sec Select specific ions Open and close in response to specific signals Different types of channels exist Voltage gated channel Ligand gated channels Mechanically gated channels  Ion channel Gene families Ligand gated channels; eg: Ach, GABA, Glycine Gap junctional channels; Seen at electrical synapses Voltage gated Na channels; Along neurons Resting membranes of glial cell is permeable to one ion Resting membranes of neurons are permeable to three  Resting membrane potential During resting membrane potential K+ diffuses out & Na + moves into the cell via: Chemical driving force Electrical driving force The two driving forces are determined by concentration gradients and the electrical potential difference As a result K+ diffuses out and Na + moves in However, Na+/K+ pump moves Na+ and K+ against their chemical gradients Resting potential is maintained by three main players 1. Na+ channels inward Na+ movement 2. K+ Channels outward K+ movement 3. Na/K pump (ATP dependent) 3Na+ ions taken out and 2K+ ions are brought in (Na/K pump’s job is to make sure that more positive ions remain outside the cell) As a result, Na+ ions are concentrated outside and K+ ions are relatively concentrated inside the cell keeping the inside negative and outside positive  During the initiation stages of an action potential: K+ channels close and Na+ ions moves in through Na+ channel and depolarization happens by becoming positive inside Now Na+ channels closes and K+ moves out through K+ channel. Next the Na/K pump brings the membrane potential to resting status Neuronal process as an electrical circuits Action Potential in myelinated fibres  Action Potential in myelinated fibres... … Action potential generated at the beginning of an axon moves through the axon passively because membrane capacitance is minimized by the myelin and the signal travels long distance When it reaches the nodes, the sodium channels fire as a result of less threshold for initiating depolarization due to Low capacitance. The cycle repeats  Different types of channels Voltage gated Ca channels Voltage gated Cl channels Monovalent cation permeable channels K channels Delayed rectifier – A slow acting K channel A Ca activated K channel The A-type K+ channel – Activated rapidly by depolarization M-type K channel – A very slow acting channel  Synapses Electrical: Structural continuity exists Chemical: No structural continuity exists  Synapses Electrical: Structural continuity exists Chemical: No structural continuity exists  Synapses Chemical: No structural continuity exists Pre-synaptic terminals Synaptic vesicles (cluster in a region specialized for releasing neurotransmitters called active zone) Synaptic cleft Post synaptic terminal A chemical synapse can amplify the signal many times An example showing communications between neuron and astrocyte Neuromuscular Synapses: Ligand gated Na+ channels Voltage gated Na+ channels Morphologic types of Synapses: Type I – Usually excitatory Glutamatergic Type II – Usually Inhibitory such as GABAergic Direct and indirect gating Synaptic second messenger system cAMP system  Phosphatidyl inositol system  Memory Memory formation/acquisition and Structural plasticity Memory Consolidation Synaptic Plasticity , LTP (Long Term Potentiation) and additional forms of activity-dependent plasticity have been found, including long-term depression (LTD)19, EPSP-spike (E-S) potentiation20,21, spike-timing-dependent plasticity (STDP)22, depotentiation23–25 and de-depression25,26  During learning, reversible physiological changes in synaptic transmission take place in the nervous system, These changes must be stabilized or consolidated in order for memory to persist. The temporary, reversible changes are referred to as short- term memory (STM). Persistent changes as long-term memory (LTM). Molecular mechanisms involved in the initiation and maintenance of synaptic plasticity. Molecular mechanisms involved in the initiation and maintenance of synaptic plasticity a | Activity-dependent release of glutamate from presynaptic neurons leads to the activation of AMPA receptors (AMPARs) and to the depolarization of the postsynaptic neuron. Depolarization occurs locally at the synapse and/or by back-propagating action potentials (BPAP). b | Depolarization of the postsynaptic neuron leads to removal of NMDA (N-methyl-D- aspartate) receptor (NMDAR) inhibition, by Mg2+, and to Ca2+ influx through the receptor27. Depolarization also activates voltage-gated calcium channels, another source of synaptic calcium c | Calcium influx into the synapse activates kinases which, in turn, modulate the activity of their substrates. These substrates contribute to local changes at the synapse, such as morphological alteration through cytoskeletal regulation, or induce the transcription of RNA in the nucleus by regulating transcription factors (TFs). d | Transcribed mRNA is translated into proteins that are captured by activated synapses and contribute to stabilization of synaptic changes. VGCC, voltage-gated calcium channel. LTP or Learnining induces morphological changes in dendritic spines. a. Increase in spine head volume. b. Spine perforation c. Increase in the Number of spines And in the number of multiple spine boutons Visualization of new dendritic spine growth following LTP or Learning Detection of perforated spines and multiple spine boutons (MSB) after LTP using electron microscopy Detection of perforated spines and multiple spine boutons (MTB) after LTP Detection of changes in spines 24 hr after learning  Detection of changes in spine after 24 hrs of learning. (trace eye blink conditioning) The cytoskeleton and structural changes Long-term potentiation (LTP) and behavioural experience induce glutamate receptor trafficking into spines  Activation of extracellular signal- regulated kinase (ERK) by synaptic signalling, and downstream targets. a | Calcium influx, either through NMDA type glutamate receptors (NMDARs) or voltage- gated calcium channels (VGCCs) triggers an increase in the levels of Ras–GTP. This leads to the activation of Raf, mitogenactivated protein kinase (MAPK)/ERK kinase (MEK) and ERK, allowing phosphorylation of both nuclear and cytoplasmic ERK substrates. The precise route to Ras activation might differ depending on the neuronal cell type and/or the extracellular stimulus. b | Following its activation, ERK phosphorylates extranuclear targets such as the voltage- dependent K+ channel KV4.2 and downstream kinases such as ribosomal protein S6 kinases (RSKs). A pool of activated ERK and RSK translocates to the nucleus, where ERK phosphorylates and activates the constitutively nuclear mitogen- and stress-activated kinases (MSKs). In the nucleus, ERKs, RSKs and MSKs phosphorylate transcription factor substrates. The best-characterized of these substrates is CREB (cyclic- AMP-responsive element (CRE)-binding protein), which might be phosphorylated by MSKs, RSKs or both. It is highly unlikely that this figure represents the entire range of neuronal ERK/RSK/MSK targets, and the identification of further substrates will be of great interest.  b | Impaired performance of MEK inhibitor-treated animals in a water maze task. Mice given an intraperitoneal injection of the MEK inhibitor SL327 or vehicle control were placed in a water maze containing a hidden escape platform. The mice could learn the location of the platform by reference to distal visual cues. Both SL327- and vehicle-treated animals learned to find the platform following training. The platform was then removed and the mice were subsequently tested for their ability to remember the previous position of the platform. The figure shows a trace of the swim path of a vehicle-treated mouse and an SL327-treated animal. The vehicle-treated animal searched intensely in the area of the maze where the platform was previously positioned (the top right quadrant, viewed from above). However, the SL327- treated mouse searched aimlessly around the pool and seemed unable to remember the location of the platform. c | Ras-dependent increases in AMPAR transmission are blocked by MEK inhibitors. Infection of organotypic hippocampal slices with Sindbis virus expressing Ras(ca)–GFP (a GFP-tagged constitutively active Ras) caused an increase in AMPAR-mediated synaptic transmission in infected cells. This increase was prevented by the MEK inhibitor PD 98059, but was unaffected by the p38 MAPK inhibitor SB 203580 (upper panel). The active Ras construct did not alter NMDAR (N-methyl-D-aspartate receptor)-mediated transmission (lower panel). Importantly, the authors also demonstrated that Ras(ca)–GFP expression occludes subsequent pairing-induced LTP in infected cell Axoplasmic Transport Anterograde and Retrograde Fast and Slow transport  The axonal transport: Who does the action? Kinesin superfamily proteins (KIFs) and dynein superfamily proteins are microtubule-dependent motors that slide along microtubules  Axonal transport delivers proteins, lipids, mRNA and mitochondria to the distal synapse and clears recycled or misfolded proteins. Such transport is involved in neurotransmission, neural trophic signalling and stress insult responses. Cargoes are conveyed along the microtubule tracks in axons by motor proteins. Disturbances in axonal transport are key pathological events that contribute to neurodegeneration in Alzheimer's disease, polyglutamine diseases, hereditary spastic paraplegia, Charcot–Marie–Tooth disease, amyotrophic lateral sclerosis and Parkinson's disease. The identification of mutations in genes encoding motor proteins in patients with neurodegenerative diseases strongly supports the view that defective intracellular transport can directly trigger neuron degeneration. Axonal transport deficits might arise through various mechanisms, including defects in cytoskeletal organization, impairment of motor protein attachment to microtubules, altered kinase activities, destabilization of motor–cargo binding and/or mitochondrial energetic breakdown. Autophagy and RNA metabolism might also interfere with the efficiency of axonal transport. Axoplasmic Transport Anterograde and Retrograde Fast and Slow transport  The axonal transport: Who does the action? Kinesin superfamily proteins (KIFs) and dynein superfamily proteins are microtubule-dependent motors that slide along microtubules  Axonal transport delivers proteins, lipids, mRNA and mitochondria to the distal synapse and clears recycled or misfolded proteins. Such transport is involved in neurotransmission, neural trophic signalling and stress insult responses. Cargoes are conveyed along the microtubule tracks in axons by motor proteins. Disturbances in axonal transport are key pathological events that contribute to neurodegeneration in Alzheimer's disease, polyglutamine diseases, hereditary spastic paraplegia, Charcot–Marie–Tooth disease, amyotrophic lateral sclerosis and Parkinson's disease. The identification of mutations in genes encoding motor proteins in patients with neurodegenerative diseases strongly supports the view that defective intracellular transport can directly trigger neuron degeneration. Axonal transport deficits might arise through various mechanisms, including defects in cytoskeletal organization, impairment of motor protein attachment to microtubules, altered kinase activities, destabilization of motor–cargo binding and/or mitochondrial energetic breakdown. Autophagy and RNA metabolism might also interfere with the efficiency of axonal transport. a| Kinesin and dynein govern the axonal transport of most cargoes. Kinesin, composed of two heavy chains/two light chains, moves cargoes in the anterograde direction along axons (towards the axon tip, the plus end of microtubules). Dynein complexes, which comprise the dynein heavy, intermediate, intermediate light and light chains and several dynactin subunits (DCTN1/DCTN2), move cargoes in the retrograde direction (towards minus end). Both kinesin and dynein motor proteins have glomerular motor domain that binds to microtubules and propel cargoes along the microtubule rails by ATP hydrolyses. b| Cargoes are attached to kinesin by the motor protein’s light subunit. Dynactin complex is involved in the attachment of the cargo onto dynein. Myosin Va is involved in the transport of cargoes along actin filaments. It has two head motor domains that bind to actin microfilaments and ATP, two α-helical segments that bind to calmodulin and two glomerular tail domains that bind cargoes. Myosin Va cooperates with the microtubule motors to regulate the distribution of cargoes along the cytoskeleton  Schematic model and binding domains of KIF5 and kinesin light chain (KLC). Top, schematic model of KIF5 associating with KLC. The KIF5 dimer associates with two KLCs to form a heterotetramer. The globular motor domains of KIF5 are shown on the left, followed by the neck, stalk and carboxy (C)-terminal tail, with which KLC associates to form fanlike ends. Middle, the domain structures of KIF5 and binding sites for KLC, GRIP1 (glutamate receptorinteracting protein 1) and RNA-containing granules. KIF5 consists of motor, neck, stalk and tail domains Kinesin is composed of a kinesin heavy chain (KHC) (KIF5) dimer and kinesin light chains (KLCs) attached to the fan-like ends. KIF1A and KIF1B are monomeric. KIF2 forms a homodimer and its motor domains are in the middle. KIF3 forms a trimer: a heterodimer of KIF3A and KIF3B associated with a soluble protein, kinesin-associated protein 3 (KAP3; shown in green). KIF4 forms a homodimer. KIFC2 also forms a homodimer, but its motor domain is on the opposite side. Different Components are transported along the “rails” of microtubules in the axon Cargo-Specific Regulation of Anterograde Axonal Transport by Protein Kinases. Examples of cargoes whose anterograde axonal transport is regulated by phosphorylation. Protein kinases that have been shown to regulate the anterograde transport of specific cargoes are listed. Their molecular targets are indicated in parentheses. For many of the molecular targets, the phosphorylation site(s) have been identified (Table 1). Question marks indicate that contradicting results have been reported on the effect of the specific protein kinase on axonal transport. Cargo-Specific Regulation of Retrograde Axonal Transport by Protein Kinases. Examples of cargoes whose retrograde axonal transport is regulated by phosphorylation. Protein kinases that have been shown to regulate the retrograde transport of specific cargoes are listed, together with their molecular targets, if known. For many of the molecular targets, the phosphorylation site(s) have been identified (Table 1). For abbreviations, see Figure 1 legend.  Potential common pathogenic mechanisms underlying many diverse neurodegenerative disorders 1. Abnormal protein dynamics with protein misfolding, defective protein degradation, and aggregation; 2. Oxidative stress (OS) and formation of free radicals/reactive oxygen species (ROS); 3. Impaired bioenergetics and mitochondrial dysfunctions; 4. Fragmentation of neuronal Golgi apparatus (GAs); 5. Disruption of cellular/axonal transport; 6. Actions and mutations of molecular chaperones; 7. Dysfunction of neurotrophins; and 8. “Neuroinflammatory”/neuro-immune processes.  Taupathies Microtubule Associated Protein Tau (MAPT) Hyperphosphorylation of tau causes aggregation to an insoluble form. These hyperphosphorylated aggregated forms are called paired helical filaments (PHF) These are intracellular accumulations Direct and indirect pathological events that can contribute to tau-mediated neurodegeneration. Pathological events that can contribute to tau-hyperphosphorylation and detachment from microtubules are shown in the box on the left. The middle box shows the mechanisms that underlie the loss of normal function and toxic gain-of-function of tau, which ultimately result in impaired axonal transport and lead to synaptic dysfunction and neurodegeneration (right hand box). Aβ, amyloid-β; MT, microtubule; NFT, neurofibrillary tangle. The dynamic equilibrium of tau microtubule (MT) binding. A schematic representation of the normal dynamic equilibrium of tau, on and off the MTs, which is primarily determined by the phosphorylation state of tau. Although the presence of tau on the MTs presents a physical obstacle for vesicles and other cargoes that are moving along the axon, MT-bound tau is essential to MT integrity. Thus, relatively frequent cycles of tau–MT binding (promoted by dephosphorylation of tau) and detachment of tau from the MT (promoted by phosphorylation of tau) are needed in order to maintain effective axonal transport.  Pathological aggregation of Tau. A schematic representation of the different stages of the formation of pathological tau aggregates. a | Abnormal disengagement of Tau from the MTs and a concomitant increase in the cytosolic concentration of tau are likely to be the key events that lead to Tau -mediated neurodegeneration. Direct causes of abnormal disengagement of Tau from the MTs include an imbalance of Tau kinases and/or phosphatases, mutations of the Tau gene, covalent modification of Tau causing and/or promoting misfolding, and possibly other causes such as other post-translational modifications. b | Once Tau is unbound from the MT it becomes more likely to misfold. c | Early deposits of Tau, called ‘pretangles’, are not stained by congo red or thioflavine-T, indicating that these intermediate forms of aggregated Tau do not exhibit the pleated b-sheet structure typically found in amyloid aggregates. d | A structural transition leads to this more organized aggregate and the eventual development of neurofibrillary tangles (e). Such transitions may be facilitated by heterogeneous interactions with membranous structures. MT, microtubule; NFT, neurofibrillary tangle; PHF, paired helical filament.  Disorders affecting axonal transport 1. Defects in axonal transport are early pathogenic events in a number of human neurodegenerative diseases. 2. Disruption to axonal transport can occur via a number of routes. These disruptions include damage to (a) molecular motors, (b) microtubules, (c) cargoes (such as inhibiting their attachment to motors), and (d ) mitochondria, which supply energy for molecular motors. 3. Age-related damage to mitochondria may amplify any primary defects to axonal transport. In this way, disruption to mitochondria may explain why many neurodegenerative diseases are diseases of old age. Collapsin Response Mediated Protein (CRMP2 ) Hirokawa et al., 2005 Nature Reviews Neuroscience. Collapsin Response Mediated Protein (CRMP2 ) Arimura et al 2005 Mol. Cell. Biol.  Anti-phospho Thr 555 CRMP2. Menon et al 2011 Mol. Cell. Prot A2M – Alpha 2 macroglobulin gene Lpr - Lymphoproliferation  Mechanisms of axonal transport defects: damage to molecular motors. (a) Kinesin and cytoplasmic dynein are the main microtubule-based motors. (b) Mutations in kinesins or cytoplasmic dynein that inhibit their activity (or are predicted to do so) cause some familial forms of ALS , hereditary spastic paraplegia (HSP) (KIF5A), and Charcot-Marie-Tooth disease (CMT) (KIF1Bβ). Furthermore, Loa and Cra mice that carry mutations in dynein heavy chain (DHC) exhibit axonal transport defects and develop MND. Phosphorylation (stars) of kinesin 1 inhibits its activity at multiple levels. (Loa: Legs at odd angle; Cra: Cramping 1) (c) Phosphorylation of KLC by a p38-dependent pathway inhibits mitochondria-bound kinesin 1 activity without affecting its binding to microtubules or mitochondria.(d ) By contrast, mutant presenilin-induced phosphorylation of KLC by GSK3β inhibits kinesin 1–mediated transport of vesicles by disrupting attachment of kinesin 1 to vesicles. (e) Finally, phosphorylation of KHC by JNK inhibits kinesin 1–mediated vesicle transport by impeding the interactions of KHC with microtubules; JNK is activated by disease-associated signals including expanded polyglutamines (Poly-Q). Cytoplasmic dynein activity may also be regulated by phosphorylation  Mechanisms of axonal transport defects: damage to microtubules. Microtubules are highly dynamic structures that undergo rapid periods of growth and shrinkage, and their dynamic behavior is regulated by several mechanisms. Deregulation of these dynamic properties may lead to disruption of cargo transport. (a) Destabilization of microtubules by decreased binding of GSK3β and/or cdk5/p35-induced hyperphosphorylated tau may lead to a loss of microtubule “rails” for transport (left). Loss-of-function mutant spastin and mutant VAPB induce abnormal bundling of microtubules to misdirect transport (right). (b) Because short microtubules are preferentially transported, mutant spastin/atlastin and VAPB may damage axonal transport of microtubules themselves. This could happen via inhibition of microtubule severing by mutant spastin or microtubule bundling by VAPB/Nir. (c) FTDP tau may damage transport by interfering with the interaction of kinesin 1 with microtubules. (d ) Finally, mutant huntingtin may induce deacetylation of α-tubulin and subsequent release of motors from microtubules.  Retrograde transport Dynein: Axonemal and Cytoplasmic Axonemal: Heavychain- a globular motor domain Intermediate chain Light intermediate Light chain  The signalling endosome. The main mode of retrograde neurotrophin signalling is through the retrograde transport of a membrane- enveloped ligand–receptor complex with characteristics of early endosomes. The mechanisms responsible for the nucleation of these complexes remain unresolved. Akt, v-akt murine thymoma viral oncogene homologue, also known as protein kinase B; ARMS, ankyrin-rich membrane-spanning protein; B-Raf, v-raf murine sarcoma viral oncogene homologue B1; CRKL, v-crk sarcoma virus CT10 oncogene homologue; C3G, Rap guanine nucleotide exchange factor (GEF) 1; EEA1, early endosome antigen 1; GAB1, GRB2 (growth factor receptor-bound protein 2)-associated binding protein 1; p85, regulatory subunit of phosphatidylinositol3-kinase; p110, catalytic subunit of phosphatidylinositol 3- kinase; Shc, Src homology 2 domain-containing transforming protein C. 1. Defects in axonal transport are early pathogenic events in a number of human neurodegenerative diseases. 2. Disruption to axonal transport can occur via a number of routes. These disruptions include damage to (a) molecular motors, (b) microtubules, (c) cargoes (such as inhibiting their attachment to motors), and (d ) mitochondria, which supply energy for molecular motors. 3. Age-related damage to mitochondria may amplify any primary defects to axonal transport. In this way, disruption to mitochondria may explain why many neurodegenerative diseases are diseases of old age.  Every signalling pathway consists of: 1. A receptor protein that specifically binds a hormone or other ligand 2. A mechanism for transmitting the ligand-binding event to the cell interior 3. A series of intracellular responses that may involve the synthesis of a second messenger and/or chemical changes catalyzed by kinases and phosphatases. These pathways often involve enzyme cascades, in which a succession of events amplifies the signal.  Pancreatic Islet Hormones Control Fuel Metabolism Exocrine gland Dedicated to producing digestive enzymes—such as trypsin, chymotrypsin, RNase A, α-amylase, and phospholipase A2—that are secreted via the pancreatic duct into the small intestine Islets of Langerhans ∼1 to 2% of pancreatic tissue consists of scattered clumps of cells known as Islets of Langerhans, which comprise an endocrine gland that functions to maintain energy homeostasis. 1. The α cells secrete glucagon (29 residues). 2. The β cells secrete insulin (51 residues). 3. The δ cells secrete somatostatin (14 residues). RSK – Ribosomal S6 Kinase REDD – regulated in development and DNA damage RagA and B – ras related GTP binding protein A and B Striated Muscle: Human biceps muscle Striated Muscle tissue, - Human biceps muscle, Consists of long fine fibres. Each fibre is a bundle of finer myofibrils. Myofibril are filaments of the myosin and actin proteins. Myosin and Actin filaments slide past one another as the muscle contracts and expands. On each myofibril, Z lines are seen. At Z line, actin and myosin filaments overlap. The region between two Z lines is called a sarcomere Sarcomeres can be considered the primary structural and functional unit of muscle tissue.  Consists of long fine fibres. Each fibre is a bundle of finer myofibrils.  Each fibre is a bundle of finer myofibrils. Myofibril are filaments of the myosin and actin proteins. Myosin and Actin filaments slide past one another as the muscle contracts and expands. On each myofibril, Z lines are seen. At Z line actin and myosin filaments overlap. The region between two Z lines is called a sarcomere Sarcomeres can be considered the primary structural and functional unit of muscle tissue.