Lecture 17 Cell Communication I 2023.pdf

Cell Communication and Signalling I 1 Forms of Intercellular Signalling Contact-dependent signalling: • Signal molecule remains bound to cell surface. • e.g. development, immune response. Paracrine signalling: • Secretion of signal molecule. • Diffuse short distances with local effects. 2 Form...

Cell Communication and Signalling I 1 Forms of Intercellular Signalling Contact-dependent signalling: • Signal molecule remains bound to cell surface. • e.g. development, immune response. Paracrine signalling: • Secretion of signal molecule. • Diffuse short distances with local effects. 2 Forms of Intercellular Signalling Synaptic signalling: • Signal molecules are delivered to target cells by cell extensions and across chemical synapses. • e.g. neurons. Endocrine signalling: • Hormones secreted into blood. • Slow signalling process. 3 Cell-Surface Receptors • • 1. 2. 3. 3 major classes of receptor proteins transform an extracellular binding event into an intracellular signal. This is called “signal transduction”. Ion-channel-linked receptors (i.e. extracellular ligand gated ion channels, or ionotropic receptors). G-protein-coupled receptors (metabotropic receptors). Enzyme-linked receptors (e.g. growth factor binding, autophosphorylation). 4 Cell-Surface Receptors 5 Ion-Channel-Linked (Ionotropic) Receptors • Composed of several subunits with multiple transmembrane segments. • Localized at specific sites in the plasma membrane (synapse). • Reversibly bind chemical neurotransmitters (i.e. the “signal molecule”) that induce a conformational change. • Channel opens, and ions move down their electrochemical gradient. • Thus, binding to receptor leads directly to a change in membrane permeability or conductance, and excitability. From Fig. 15-15A Alberts et al. 6 Neurotransmitters • Neurotransmitters are chemicals produced in the cytosol of a neuron, usually in the presynaptic terminal. • Biosynthetic enzymes for these reactions are produced in the cell body and delivered throughout the cell by slow axoplasmic flow. • Neurotransmitters are stored in synaptic vesicles for rapid release when necessary. • Some neurotransmitters, called neuropeptides, are sorted through the ER and Golgi (as are other soluble proteins) and delivered to the cell periphery by fast axonal transport. 7 Signalling at a Chemical Synapse • The synapse: specialized site of chemical communication between 2 electrically isolated cells. • In the nervous system, a presynaptic cell associates with a postsynaptic cell. • Neurotransmitters released from the presynaptic cell cross the synaptic cleft and bind to postsynaptic receptors. 8 Signalling at a Chemical Synapse 9 Excitatory or Inhibitory Chemical Synapses Excitatory • Activation leads to net gain of positive charge. • Increases excitability of the cell (i.e. its ability to depolarize). • e.g. glutamate, acetylcholine. Inhibitory • Activation leads to net loss of positive charge. • Decreases excitability. • e.g. GABA (g-aminobutyric acid), glycine. 10 The Neuromuscular Junction • Synaptic interaction between motor neuron and skeletal muscle cell. • Well-studied model of gating of ionotropic receptors by ACh. Skeletal muscle cell of frog Fig. 11-34 Alberts et al. 11 Acetylcholine (ACh) Receptor • • • • Contains 5 transmembrane subunits (a,a,b,g,d), 2 of which are identical and form ACh-binding sites. Subunits arranged in a ring forming a water-filled pore. These channels have little ion selectivity, but negatively-charged amino acids near the pore promote passage of positively-charged ions (e.g. Na+, K+). Gated by hydrophobic side chains of 5 leucines. 12 Acetylcholine (ACh) Receptor • 2 ACh molecules must bind to both a subunits for channel to open. • Na+ and K+ flow in opposite directions, but the stronger inward driving force of Na+ will produce a net gain of (+). No ACh bound: Channel closed 2 AChs bound: Channel open EK = -80 mV ENa = +60 mV Em = -70 mV 13 From Fig. 11-13 Kandel et al. 2000 SEM Image of AChR • Postsynaptic membrane of cell from electric fish. • Membrane is partially obscured by basal lamina. • Basic structure of AChR can be seen. Electrocyte from electric organ of Torpedo Fig. 9.2 Squire et al. 2003 14 ACh Receptors in Muscle Contraction 1. 2. 3. 4. 5. A nerve impulse reaches the synaptic terminal of a presynaptic neuron causing influx of Ca2+ and release of ACh into the synaptic cleft. ACh binds to postsynaptic receptor and induces local influx of Na+ and depolarization. Voltage-gated Na+ channels open and further depolarize the cell. Voltage-dependent effect on plasma membrane Ca2+ channel in T-tubule. Opening of Ca2+ release channel in SR causes increase in cytosolic Ca2+ and muscle contraction. 15 ACh Receptors in Muscle Contraction Note: this occurs during contraction of skeletal muscle. The situation is different for cardiac muscle contraction. 16 Glutamate Receptors • Main excitatory neurotransmitter in the mammalian central nervous system. • Therefore, many excitatory synapses utilize glutamate receptors at the postsynaptic membrane. • Divided into 2 types, based on the type of synthetic agonist that activates them: – NMDA (N-methyl-D-aspartate) – non-NMDA (activated by AMPA and kainate). • Basic structure and function similar to ACh receptors. • However, NMDA receptors are also voltage-gated. 17 Glutamate Receptors • • • • Both receptor types depend on glutamate for activation. Both are permeable to Na+ and K+. However, NMDA receptors also require glycine for activation, are permeable to Ca2+, and are regulated by many other factors. Importantly, NMDA receptors are blocked by Mg2+ inside the pore until the membrane is depolarized and Mg2+ is displaced. Non-NMDA From Fig. 12-5A Kandel et al. 2000 NMDA 18 Role of Glutamate Receptors in Learning • Glutamate receptors play a major role in learning and memory. • Located in mammalian hippocampal neurons. • Short “bursts” of activity from presynaptic neurons can have long-lasting effects on the glutamate sensitivity of postsynaptic receptors. • This process is believed to underlie learning and is called “long-term potentiation” and can last hours, days or weeks. 19 Long-Term Potentiation (LTP) 1. 2. 3. 4. Both pre- and postsynaptic cells are at rest. Membranes are polarized. Glutamate released by presynaptic cell into synaptic cleft binds to both NMDA and non-NMDA receptors. Na+ influx occurs via non-NMDA receptors and depolarizes postsynaptic membrane. Depolarization displaces Mg2+ from pore of NMDA receptors and Ca2+ influx takes place. Increased Ca2+ initiates intracellular pathway that leads to increased delivery of non-NMDA receptors to the plasma membrane. 20 Long-Term Potentiation (LTP) 1 2 3 4 Increased non-NMDA receptor expression A GRP, called cAMP response element binding protein (CREB), appears to be involved. 21