Signaling in CNS in Health & Disease PDF

Signaling in CNS in health & disease DTBS Martine Smit 1 Signaling in the CNS I - Signaling in health – Classical neuronal si...

Signaling in CNS in health & disease DTBS Martine Smit 1 Signaling in the CNS I - Signaling in health – Classical neuronal signaling Neuronal communication Chemical mediators involved in signaling CNS – Acetylcholine (ACh), noradrenaline (NA) – Glutamate, GABA – Learning and memory II - Signaling in disease DTBS – Neurodegenerate diseases Alzheimer’s disease: drug targets 2 1  Neuronal signaling via release of neutransmitters Presynaps DTBS Postsynaps 3 Neuronal signaling Nerve terminal: - depolarisation opens Ca2+ channel - Ca2+ responsible for NT release - generation new vesicles - interaction autoreceptor* - removal NT - uptake/breakdown NT Post synapse: - interaction ion channels DTBS - interaction GPCRs Red square = NT = neurotransmitter; * autoreceptor (on presynaps not depicted) 4 2  Neuronal signaling via release of neutransmitters Presynaps DTBS Postsynaps 5 Integration signaling output DTBS 70% of brain: inhibitory function Q what defines propagation/inhibition of the signal? 6 3  Synapses and neuronal integration Two types of synapses – Excitatory excitatory postsynaptic potential (EPSP) – Inhibitory inhibitory postsynaptic potentials (IPSPs) DTBS Q – which events/proteins are responsible for EPSP/IPSP? 7 Synapses and neuronal integration Two types of synapses – Excitatory excitatory postsynaptic potential (EPSP) depolarisation – via Na+ influx – after e.g. acetylcholine, glutamate binding to their respective receptors – Inhibitory inhibitory postsynaptic potentials (IPSPs) hyperpolarisation - via e.g. increased K+ and Cl- influx DTBS - after e.g. GABA binding to the GABA receptors 8 Q – role synapses? 4  Different types of neurotransmitters DTBS Q – to which type of receptors do these neurotransmitters bind to? 9 Neuronal signaling by distinct neuronal networks DTBS 10 5  Chemical mediators in CNS Neurotransmitters – from cell to cell Fast via ion channels (e.g. Acetylcholine (ACh), GABA, glutamate) Slow via GPCRs (e.g. Noradrenaline (NA), Acetylcholine (ACh), dopamine (DA)) DTBS 11 Chemical mediators in CNS Neurotransmitters – from cell to cell Fast via ion channels (e.g. Acetylcholine (ACh), GABA, glutamate) Slow via GPCRs (e.g. Noradrenaline (NA), Acetylcholine (ACh), dopamine (DA)) Neuromodulators – Neuronally released or from other cells E.g. neuropeptides, histamine, nitric oxide (NO), archidonic acid (AA) Mainly via GPCRs – Slow responses, more general action – Effect on gene transcription ‘Synaptic plasticity’(role learning memory) DTBS Neurotrophic factors – Growth/morphology of neurons Mainly via tyrosine kinases 12 6  Control cellular processes sympathetic vs parasympathetic DTBS Q – which type of neurotransmitter control these processes? 13 Cholinergic transmission DTBS 14 7  Action acetylcholine (ACh) Effects – Cholinergic neurons widely distributed through the brain eg role in memory – Lowering blood pressure, slowing heart rate Indirect via NO release – Choline vs acetylcholine Acetylcholine much more effective – Two types of activity muscarinic DTBS nicotinic 15 Membrane-bound receptors acetylcholine recognition HO CH3 CH3 N+ H3C O CH3 muscarine O CH3 CH3 N+ H3C O CH3 acetylcholine DTBS N+ H CH3 N nicotine Nicotiana Tabacum 16 8  Membrane-bound receptors acetylcholine recognition HO Muscarine m1-m5 receptors (GPCRs) CH3 mAChRs CH3 N+ H3C O CH3 muscarine O CH3 CH3 N+ H3C O CH3 acetylcholine Nicotine receptors (ion channels) nAChRs DTBS N+ H CH3 N nicotine 17 Ion channel opening At nerve pulse: 100-500 vesicles released - Na+ influx - excitatory - depolarisation DTBS 18 9  Ligand-gated ion channels unique composition subunits Muscular nAChR Neuronal nAChR Neuronal nAChR DTBS Heteropentamers Heteropentamers Homopentamers 19 Role subtypes nAChRs in CNS disease DTBS Subtypes differ in: – Subunit composition subtype-selective ligands needed: – Ligand pharmacology molecular tools to characterize subtypes – Cation permeability effective and save drugs – Distribution 20 10  Cholinergic transmission nAChRs (ion channels) and mAChRs (GPCRs) DTBS 21 Noradrenergic signaling DTBS = noradrenaline Q – what negative feedback mechanism exist? 22 11  Noradrenergic signaling DTBS = noradrenaline Q – what negative feedback mechanism exist? 23 Re uptake neurotransmitter (NA) NA metabolised - 75% of NA restored - specific NA transporter (NET) DTBS 24 12  Negative feedback ➤ control NA release a2 receptor autoreceptor inhibition cAMP decrease Ca2+ uptake decrease release NA common mechanism other neurotransmitters DTBS Note: increased calcium in presynaps leads to enhanced NA release 25 Neuronal signaling via amino acids Glutamate, glycine and GABA as fast neurotransmitters – Different mode of action: Glutamate and other acidic amino acid excite neurons Presence of GABA in brain, inhibitory effect Synthesis throughout body HOOC – Basic role in metabolism HOOC HOOC – Selective carriers for uptake DTBS COOH H2 N H2N H2N glutamate GABA glycine 26 13  Glutamate receptors iGluRs (ionchannels) + mGluRs (GPCRs) DTBS 27 Ionotropic glutamate receptors iGluRs Main subtypes – Ionotropic glutamate receptors (iGluRs): NMDA, AMPA, kainate Ligand-gated ion channels named after synthetic agonist Multimeric proteins Allosteric regulation! (e.g. glycine at NMDA receptor) AMPA receptors are mostly responsible for fast EPSPs DTBS 28 14  Ligand-gated NMDA receptors Allosteric modulation by glycine DTBS 29 Metabotropic glutamate receptors mGluRs – Metabotropic receptors (Class C GPCRs): mGluRs 8 different GPCRs Very long N-terminal tail, which binds glutamate Gq coupled (IP3-calcium) or Gi coupled (inhibition of adenylyl cyclase) – Postsynaptic activation Class C GPCRs – Presynaptic inhibiton DTBS 30 15  Metabotropic Glutamate receptors mGluRs DTBS Q – which part of mGluRs to targets? 31 Glutamate receptors iGluRs and mGluRs are involved in: – Role in learning and memory – Long Term Potentiation (LTP): – Long-lasting enhancement signal transduction between 2 neurons o stimulating them synchronously – Synaptic plasticity o The ability of chemical synapses to change their strength DTBS – Memories encoded by modification of synaptic strength 32 16  Glutamate and LTP DTBS LTP: strengthening the connections between neurons ➤ role in learning and memory 33 DTBS ➤ memory encoded by modification of synaptic strength 34 17  Synapses and neuronal integration Function synpases – Process information, store it, make decisions – Chemical synapses decision-making devises of CNS – More activity in synapses spine enlargement ➤ LTP maintainance more information processing DTBS 35 Dendritic spines dysgenesis brain disorders DTBS ➤ Lower number of spine densities and/or atypical morphologies 36 18  Long-term potentiation - memory encode, store, retrieve optogenic control transgenic mice DTBS Scaffolding PDZ containing proteins at Post synaptic density (PSD) 37 19