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實驗神經概論 楊定一 老師 Course Outline 1. 2. 3. 4. 5. 6. Plasma membrane Intracellular organelles 2.1 Nucleus; 2.2 Mitochondria; 2.3 Endoplasmic reticulum 2.4 Golgi; 2.5 Lysosome; 2.6 Peroxisome Cytoskeleton Cell signaling Cell cycle and cell lineage Cell types in nervous systems A more realistic view of an eukaryotic cell. A simplified carton of an eukaryotic cell. 1. Plasma membrane • Functions • Structural components: phospholipids membrane proteins integral membrane proteins peripheral membrane proteins membrane cytoskeleton General structure and components of cellular plasma membrane Functions of plasma membrane • A boundary to hold the cell constituents together and to keep other substances from entering, thus forming a semi-porous barrier to the outside environment. • Selective permeability: small molecules (oxygen, carbon dioxide, and water) pass freely, larger molecules (amino acids, proteins, sugars and DNA/RNA) pass under regulation. This is accomplished by membrane proteins. Functions of membrane proteins • Selective transport of certain substances (as channels or active transport molecules). • Receptors binding to information-providing ligands (such as hormones) to transmit signals. • Enzymatic activity: catalyzing various reactions related to the plasma membrane. 2. Intracellular Organelles 1. Plasma membrane controls movement of molecules in and out of the cell and functions in cell-cell signaling and cell adhesion. 2. Mitochondria generate ATP by oxidation of glucose and fatty acids. 3. Lysosomes with an acidic lumen degrade material internalized by the cell and worn-out cellular membranes and organelles. 4. Nuclear envelop (double layer) encloses the contents of the nucleus; the outer nuclear membrane is continuous with the rough ER. 5. Nucleolus is a nuclear sub-compartment where most of the rRNA is synthesized. 6. Nucleus is filled with chromatin composed of DNA and proteins. 7. Smooth endoplasmic reticulum (ER) synthesizes lipids and detoxifies certain hydrophobic compounds. 8. Rough ER functions in the synthesis and sorting of secreted proteins, lysosomal proteins, and some membrane proteins. 9. Golgi complex sorts secreted proteins, lysosomal proteins, and membrane proteins synthesized on the rough ER. 10. Secretory vesicles store and release secreted proteins. 11. Peroxisomes detoxify various molecules and break down fatty acids to produce acetyl groups for biosynthesis. 12. Cytoskeletal fibers form networks to support cellular membranes, organize organelles, and participate in cell movement. 13. Microvilli increase surface area for absorption of nutrients from surrounding medium. 2.1 Nucleus • The nucleus, the largest organelle in animal cells housing the genome of a cell, is surrounded by two membranes, each one is composed of a phospholipid bilayer containing many different types of proteins. • The inner and outer nuclear membranes are fused at numerous nuclear pores, through which materials pass between the nucleus and the cytosol. The outer nuclear membrane is continuous with that of the rough ER. The nucleolus (n) is a subcompartment of the nucleus (N) without membrane and produce most rRNA. Heterochromatin is the condensed and concentrated DNA. The ribosomal subunits as well as tRNAs and mRNA-containing particles pass through a nuclear pore into the cytosol for protein synthesis. 2.2 Mitochondria • A mitochondrion (複數 mitochondria) is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 10 micrometers (mm) in diameter. • Mitochondrion comes from the Greek word meaning mitos (thread) + chondrion (granule). Therefore, 粒線體 is correct, but粒腺體 is wrong! A mitochondrion Some characteristics of mitochondria • The number of mitochondria in each cell varies. • Neurons have mitochondria throughout its whole structures, including soma (cell body), dendrites, and terminal synapses. • Mitochondrial DNA and symbiosis. Structures of mitochondria • Outer and inner membranes with different properties. • Five distinct compartments in a mitochondrion: – – – – – outer mitochondrial membrane intermembrane space inner mitochondrial membrane crista space (formed by infoldings of the inner membrane) matrix (space within the inner membrane) Functions of mitochondria • Production of ATP by oxidizing the major products of glucose, pyruvate, and NADH (reducing power) in the presence of oxygen • Heat production • Calcium storage in the mitochondrial matrix • Apoptosis by releasing cytochrome C and other proapoptotic proteins into cytosol Oxidative phosphorylation to produce ATP 2.3 Endoplasmic reticulum (ER) • Synthesis of lipids (in smooth ER) as well as membrane proteins and secreted proteins (rough ER), but NOT soluble cytosolic proteins (in cytosol). See next slide. • Enzymes in the smooth ER also detoxify hydrophobic chemicals such as pesticides and carcinogens to be excreted from the body. Rough ER: flattened sheets Smooth ER: tubular structures • Rough ER is characterized by the ribosomes attached to the cytosolic (outer surface) of membrane. Smooth ER is smooth because of the absence of ribosomes attached to the membrane. 2.4 Golgi complex • Golgi complex contains three regions (cis medial trans) to process secreted and membrane proteins. 2.5 Lysosome • Lysosomes contain acid hydrolases. The name lysosome derives from the Greek words lysis, which means dissolution or destruction, and soma, which means body. • Lysosome is the garbage disposal system in a cell. • Lysosomes digest excess or worn-out organelles, food particles, and engulfed viruses or bacteria. The membrane around a lysosome allows the digestive enzymes to work at low pH (4.5). 2.6. Peroxisomes • Peroxisomes participate in the metabolism of fatty acids and other metabolites. Peroxisomes catablize toxic peroxides (過氧化物質) in the cells. 3. Cytoskeleton 1. Microtubules and motor proteins 2. Intermediate filaments (neurofilaments in neurons) 3. Microfilaments 3.1 Microtubules • Tubulins belong to GTPase protein family that polymerize to form microtubules, hollow cylindrical structures 25 nm in diameter. • Microtubules exhibit structural polarity. Subunits are added and lost preferentially at one end, the “+” end. • Assembly and disassembly of microtubules depends on the critical concentrations (CC) of ab-tubulin subunits. Above CC, microtubules assembly and below CC, disassembly. Axonal transport along microtubules in both directions • All the axonal microtubules are all oriented with their “+” ends toward the terminal (synapse). In dendrites, however, microtubules are oriented in both ends. • Anterograde axonal transport proceeds from the cell body to the synaptic terminals and is associated with axonal growth and the delivery of synaptic vesicles. • Retrograde axonal transport is in the opposite direction from nerve terminus to cell body. MTOC: microtubule organizing center Motor proteins for microtubulekinesin • Kinesin is responsible for anterograde axonal transport. Most kinesins are processive “+” enddirected movements. • The head domains of kinesin bind microtubules. The tail domains of kinesin bind to the membrane of vesicles to determine their cargos. Motor proteins for microtubuledynein • Dynein is responsible for retrograde axonal transport and other “–” end-directed movements. • Dynactin is a large protein complex that links vesicles to the dynein light chains. 3.2 Neurofilaments • cytokeratin family including glial fibrillary acidic protein (GFAP; an astrocyte marker) • 10 nm in diameter • stable polymers • 1 neurofilament 32 monomer – 8 protofilaments in each neurofilament – 4 monomers in each protofilament 3.3 Microfilaments • • • • • subunits: b- and g-actin monomer 3-5 nm in diameter polar, dynamic structure ATP With actin-binding proteins, actin filaments form a dense network lying underneath the plasmalemma. This matrix plays a key role in the formation of pre- and postsynaptic morphologic specializations. • In axon, all the microtubules are arranged with the plus end pointing away from the cell body, minus end facing the cell body. • In dendrites, microtubules with opposite polarities are mixed. microtubule neurofilament microfilament a-tubulin b-tubulin (G) cytokeratins GFAP etc (F) b-actin g-actin (G) GTP none ATP 25-28 nm 10 nm 3-5 nm dynamic but more stable in mature axons and dendrites stable and polymerized dynamic, ~ ½ of the actin in neurons can be unpolymerized 4. Cell signaling • The level of secondary messengers, such as Ca2+, cAMP, cGMP, and IP3, increases or decreases in response to binding of ligand (primary messenger) to cell-surface receptors. • These non-protein intracellular signaling molecules then regulate the activities of enzymes and non-enzymatic proteins. • Rapid termination of signaling once a particular ligand is withdrawn help cells respond appropriately under different circumstances. Examples of some second messengers. Seven major classes of cell surface receptors Amplification of an external signal downstream from a cell-surface receptor 5. Cell cycle and cell lineage • Cell cycle is divided into four major phases: G1, S, G2, M. • In cycling somatic cells, cells synthesize RNAs and proteins during the G1 phase, preparing for DNA synthesis and chromosome replication during the S (synthesis) phase. • After progressing through the G2 phase, cells begin the complicated process of mitosis (mitotic) phase. Overview of the birth, lineage, and death of cells • Two daughter cells resulting from asymmetric division differ from birth with different fates. • Asymmetric division commonly is preceded by the localization of regulatory molecules (green) in one part of the parent cell. • A series of symmetric and/or asymmetric cell divisions, called a cell lineage, gives birth to each of the specialized cell types found in a multicellular organism. • Programmed cell death (PCD) occurs during normal development and in response to infection or poison. A series of specific programmed events, called apoptosis, is activated during PCD. Stem cells give rise to stem cells and to differentiating cells (a) Division of a stem cell produces two cells, one is similar to the mother cell to maintain the population of stem cells. (b) The other daughter cell-a stem cell of more restricted potential-starts on a pathway toward producing more differentiated cells. When it divides, one of the daughters will be the same sort of restricted potential stem cell as the mother and the other will be a progenitor cell for a certain type of differentiated cell. (c) Progenitor cells can divide to reproduce themselves and can differentiate into a terminally differentiated, nondividing cell. Adult neural stem cells • Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. • Neural progenitor and stem cells were isolated in 1992 from the striatal tissue, including the subventricular zone, thus demonstrating the existence of adult NSCs. • Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens that promote neural progenitor and stem cell growth in vitro. Adult neurogenesis • In the subventricular zone (SVZ) of the lateral ventricle wall, differentiated cells migrate through the rostral migratory stream into the olfactory bulb to become interneurons. • The dentate gyrus subgranular zone (SGZ) of the hippocampus also contains neural stem cells that differentiate into interneurons. LV: lateral ventricle SGZ: subgranular zone Cell types in nervous systems • Neuron • Glia – CNS: astrocyte, oligodendrocyte, microglia – PNS: Schwann cell Functional roles of astrocytes • Providing some degree of mechanical integrity to tissue • Maintaining the composition of the extracellular milieu • Participating in synaptic function and plasticity • Providing neurotransmitters and energy substrates to neurons and cleaning up the extracellular neurotransmitters • Regulating blood flow • Formation of blood-brain-barrier (BBB) Astrocytes The above image depicts two adjacent astrocytes from the rat brain hippocampus injected with two different color dyes to elucidate their individual morphology. Another astrocyte image Red: MAP-2-positive rat cortical neurons Green: GFAP-positive rat astrocytes Oligodendrocytes and Schwann cells • Myelination is achieved by oligodendrocytes in CNS: one oligodendrocyte can myelinate several neuronal axons. • Myelination is achieved by Schwann cells in PNS: each Schwann cell myelinates one segment of axons. Oligodendrocytes and microglia Oligodendrocytes generated from mouse neural stem cells Microglia are the main resident immunological cells the CNS. This is a high-power view of two microglia stained with a silver method. Microglia • Microglia: the resident macrophages of the brain and spinal cord, act as the first and main form of active immune defense in CNS. • Microglia are constantly excavating the CNS for damaged neurons, plaques, and infectious agents. The brain and spinal cord are considered "immune privileged" organs because BBB prevents most infections from reaching the vulnerable nervous tissue. • If infectious agents are directly introduced to the brain or cross the BBB, microglial cells must react quickly to increase inflammation and destroy the infectious agents. Activated microglia: M1 and M2 • M1-type: classical and proinflammatory activationneurotoxic – M1 markers: interleukin (IL)-1β, IL-6, IL-12, IL-23, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), etc • M2-type: alternative and anti-inflammatory activation-neuroprotective – M2 markers: insulin-like growth factor (IGF)-1, triggering receptor expressed on myeloid cells 2 (TREM2), chitinase 3-like 3 (Ym-1), etc Biochem Pharmacol. 2016 Mar 1;103:1-16 A single Purkinje neuron of the cerebellum made visible by introducing a fluorescent protein. The cell body is the bulb at the bottom. Four Basic Structural Components of Neurons • Cell body (soma) contains the nucleus and is the site of synthesis of virtually all neuronal proteins and membranes. Some proteins are synthesized in dendrites but none are made in axon or axon terminals. • Axon is specialized for conduction of action potentials. • Axon terminals are small branches of the axon that form the synapses with other cells. • Dendrites extend outward from the cell body and are specialized to receive chemical signals (neurotransmitters) from the axon termini of other neurons. Dendrites convert signals into small electric impulses and conduct them toward the cell body. Typical morphology of two types of mammalian neurons Selective distribution of membranous organelles in neurons • A sharp functional boundary at the axon hillock, certain organelles are absent in axon – protein biosynthetic machinery (ribosomes, rough ER, Golgi complex). – lysosomes • Axons are rich in – synaptic vesicles – endocytic intermediates involved in synaptic vesicle traffic – synaptic vesicle precursor membranes • Mitochondria and smooth ER (Ca2+ regulation) are present in all neuronal compartment including axon. Voltage-gated ion channels and propagation of action potentials • Neurons are specialized to generate and conduct a particular type of electric impulse, the action potential. • Action potential is a series of sudden changes in the voltage (or equivalently electric potential) across the plasma membrane caused by the opening and closing of certain voltage-gated ion channels. • Electric signals (action potential) carry information within a nerve cell, while chemical signals (neurotransmitters) transmit information from one neuron to another or from a neuron to other target cell. Arrival of action potential triggers opening of voltage-sensitive calcium channels, causing calcium influx and thus fusion of small vesicles containing neurotransmitters with plasma membrane, thereby releasing neurotransmitters into synaptic cleft. Myelination • Myelin sheath is a stack of specialized plasma membrane sheets produced by a glial cell that wraps itself around the axon. • Myelination is achieved by Schwann cells in peripheral nervous system and oligodendrocytes in central nervous system. Myelination increases the velocity of impulse conduction • In non-myelinated neurons, the conduction velocity of an action potential is roughly proportional to the diameter of the axon. A thicker axon will have greater numbers of ions that can diffuse. • In myelinated neurons, the presence of myelin sheath around an axon increases the velocity of impulse conduction up to 100 fold. • Node of Ranvier Node of Ranvier • The myelin sheath surrounding an axon is formed from many glial cells. • Each region of myelin formed by an individual glial cell is separated from the next region by an unmyelinated area of axonal membrane about 1 mm in length called Node of Ranvier. • All the voltage-gated Na+ channels and all the Na+/K+ pumps are located in the nodes for regeneration of action potential. Action potential spread passively through the axonal cytosol to the next node with very little loss or attenuation, because ions cannot cross myelinated axonal membrane. In effect, the action potential “jump” from node to node. Composition of myelin • Basic phospholipid bilayer structure with far fewer types of proteins than found in other membranes. • Peripheral myelin proteins: P0 (causes adjacent plasma membranes to stack tightly together) and PMP22. • In the central nervous system, a different membrane protein and a proteolipid together function similarly to P0. • The major cytosolic protein in all myelin sheaths is myelin basic protein (MBP). MS: myelin sheath