Molecular biology of neural communication

Molecular biology of neural communication

One picture - two information

Where do I feel the pain?

Real and Virtual Consciousness Almost all neural process is pervaded by the consciousness We not only perceive the incoming information, but also interpret and subjectively experience them Consciousness produces a virtual world, which is believed to be real

0 Hierarchy of neural processing Neuron neural centers neural networks consciousness

Structure of the talk 1. Introduction 2. Operation of a neuron 3. Communication between neurons

Introduction

1a Local and distant communication between animal cells

1b Modes of signal transmission Hormone system Nervous system

2 The reticular - versus neuron doctrine Nobel Price: 1906 Camillo Golgi Santiago Ramón y Cajal

3 Complexity of nervous system Human brain Number of neurons: 3-5 x 10 11 Number of synapses/neuron: 10 4 Total number of synapses: 3-5 x 10 15 Synaptic plasticity The response of a neuron to a stimulus depends on its internal state, which under a complicated control

4 Types of neurons Interneurons sensory neuron motor neuron local projection

Operation of a neuron a. Resting potential b. Transport proteins c. Action potential

Resting potential

5 Migration of charged particles Lower concentration Passive Active Induced by 3 factors: 1. Concentration gradient 2. Electrical gradient 3. Ion pump Higher concentration Positive side Negatíve side

6 Donnan equilibrium Outer space Semipermeable membrane Inner space + + + + + - - + + - - + + + + + + + + + + - - +

7 Steady state for K-ions (dynamic constancy) A hypothetical cell: only can freely move Initial state CELL EXTERIER

8 Steady state for (dynamic constancy) A hypothetical cell: only can freely move Steady state CELL EXTERIER

9 Equillibrium potential - steady state for

10 Resting potential Definition: The resting potential is the voltage across the plasma membrane of an excitable unstimulated cell.

11 Resting potential Plasma membrane Voltmeter 70 mv Microelectrode outside the cell Microelectrode inside the cell Axon Neuron

Transport proteins

12 Types of transport proteins A. Ion channels passive transport I. Specific channels -, Na +, Ca 2+, Cl - II. Cation-selective channels B. Ion pumps active transport

12 Types of transport proteins A. Ion channels passive transport I. Leaky channels - nonregulated II. Gated channels - regulated - Voltage-gated channels - Ligand-gated channels - Phosphorylation-gated channels - Stretch-gated channels - Gap junction channels B. Ion pumps active transport

13 Gated ion channels Ligand-gated Voltage-gated Phosphorylation-gated Gate Stretch/pressure-gated

14 Gap junctions Gap junction

15 Na + - -pump Extracellular space ATP Cytoplasm Na + Na + High K+ permeability Na + Na + Na + Na + Na + Na + Na + Low Na+ permeability Na + Na +

16 Na + /Ca + -channels Channel pore S1 S2 S3 S4 S5 S6 H5 S4 segment: voltage sensor -subunit

17 Na + -channel

18 -channels Channel pore S1 S2 S3 S4 S5 S6 H5 S4 segment: voltage sensor

19 Extended -channel family Depolarization-activated, non-inactivating channel Depolarization-activated, inactivating channel Depolarization- and Ca 2+ - activated channel Cyclic nucleotid-activated cation channel Inward rectifier channel

20 Operation of voltage-gated ion channels Activation gate Inactivation gate

21 Operation of voltage sensors Na + Na + Na + Na + Na + Na + Voltage sensors Activation gate

Action potential

22 Excitation, EPSP EPSP: excitatory post-synaptic potential

23 Inhibition, IPSP EPSP: excitatory post-synaptic potential IPSP: inhibitory post-synaptic potential

24 Excitation, inhibition IPSP EPSP Action potential IPSP EPSP

25 Excitation - inhibition Na + Na + Cl - Cl - Cl - Cl - Outer space Na + Na + + + + + + + + + + + + + + Cell membrane Depolarization - - - - - - - - - - - - - - - Intracellular millieu

26 Excitation - inhibition Na + Na + Cl - Cl - Cl - Cl - Outer space Na + Na + + + + + + + + + + + + + + + + + Cell membrane Hiperpolarization - - - - - - - - - - - - - - - - - - - - - - Intracellular millieu

27 Sapatio-temporal summation Spatial summation Temporal summation

28 The all-or-none principle IPSP EPSP Action potential IPSP EPSP

29 Progression of action potential Axon Action potential 1 Na + Axon segment Action potential 2 Na + Action potential 3 Na +

30 Progression of action potential 3 Na + 4 Further Na + channels open, the channels are still closed 2 Na + Na+ Action potential Axon hillock 3 The Na + channels become closed, the channels open Na+ A stimulus can open some Na+ channels; if it exceeds the threshold: action potential will be generated 2 Threshold potential 1 Resting potential 4 5 6 5 The channels slowly become closed: short undershoot 1 Axon 6 Return to resting state Resting state: voltage-gated Na + and channels are closed

31 Progression of action potential Resting state Depolarization Repolarization Undershoot

32 Progression of action potential

33 Saltatory conduction

34 Travelling signals

Communication between neurons a. Synaptic signal transmission b. Receptors c. Signal transduction in neurons d. Neuromodulation

Synaptic signal transmission

35 Traveling signals

36 Imputs of a neuron Dendrites Synaptic nodes Myelin sheath Axon Receiving cell body Synaptic nodes

37 Types of synapses-i Electric synapses Chemical synapses

38 Types of synapses-ii

39 SENDING NEURON Vesicles Synaptic knob 1 Action potential arrives 2 3 Vesicle fuses with plasma membrane 4 Neurotransmitter is released into synaptic cleft Ca ++ Operation of synapses 5 Ca + enter the cells SYNAPTIC CLEFT RECEIVING NEURON Ion channels Ions Neurotransmitter Receptor Neurotransmitter molecules Neurotransmitter binds to receptor Neurotransmitter broken down and released 6 Ion channel opens 7 Ion channel closes

40 Neurotransmitters I. Biogen amines Histamin Serotonin Dopamine Norepinephrine catecholamines Adrenaline Monoamines II. Aminoacids Glutamate, aspartate, glicine, GABA III. Peptides Substance P, enkephalins, endorphins, angiotensin, somatostatin, vasopressin IV. Acetylcholin V. Other transmitters NO, CO, ATP, H +

Receptors

41 Types of receptors Metabotropic receptors Ionotropic receptors - Direct gating of ion flow - Indirect gating of ion flow - Fast effect - Slow effect

42 Types of receptors N + N + N + N +

43 Ionotropic receptors: ligand-gated ion channel receptors Nicotinic receptor Glutamate receptor ATP receptor superfamily superfamily superfamily 4 segmenst 3 segments 2 segments P2X and ASIC receptors 5 subunits 4 subunits 3 subunits

44 G protein-coupled receptors - metabotropic receptors

Signal transduction in neurons

Nobel Díj: 2000 Nobel Prize signal transduction in the nervous system Arvid Carlsson Paul Greengard Eric R. Kandel

45 Signal transduction in neurons

46 Signal transduction in neurons

GDP 47 Adenylyl cyclase second messenger system Metabotropic receptor Adenylyl cyclase Ion channel R CELL MEMBRANE AC I C G s protein PK Protein kinase A

GDP GTP 47 Adenylyl cyclase second messenger system Metabotropic receptor Adenylyl cyclase Ion channel R CELL MEMBRANE AC I C PK Protein kinase A

GDP GTP 47 Adenylyl cyclase second messenger system Metabotropic receptor Adenylyl cyclase Ion channel R CELL MEMBRANE cam P AC I C P AT P cam P PK Protein kinase A

GTP 47 Adenylyl cyclase second messenger system Metabotropic receptor Adenylyl cyclase Ion channel CELL MEMBRANE R AC I C P cam P Protein kinase A PK

GDP GTP 47 Adenylyl cyclase second messenger system Metabotropic receptor Adenylyl cyclase Ion channel CELL MEMBRANE R AC I C

GDP 48 Phosphoinositide second messenger system Metabotropic receptor Phospholipase C Potasium ionchannel R CELL MEMBRANE PIP2 Protein kinase C DAG PK P I C Calmodulin kinase II CaMKII G q protein K+ CaM P ER IP3 IP3 receptor Ca 2+ CaM Ca 2+ PIP2:phosphatidyl inositol-4,5-biphsophate IP3: inositol-1,4,5-triphosphate DAG: diacylglycerol CaM: calmodulin

49 Signal transduction cascade

Neuro-modulation

50 Inhibition A on presynaptic neuron Inhibition of transmitter release a variety of mechanisms B on postsynaptic neuron i.p.s.p

51 Auto-receptors Pre-synaptic neuron Ionotropic receptor Ionotropic receptor Post-synaptic neuron

52 Metabotropic receptor modulation

53 Neurotransmitter deactivation Antidepressants: Selective serotonin reuptake inhibitors (SSRIs) 1. Reuptake Neurotransmitter reuptake pump Monoamino oxidase (MAO) inhibitors Acetylcholin estherase 2. Inactivating enzymes 3. diffusion

Long term potential

54 Hippocampus Thalamus CEREBRUM Hypothalamus Prefrontal cortex Olfactory bulb Amygdala Hippocampus

55 Hippocampus

56 Long-term potential (LTP) Schaffer collateral CA1 NMDA, non-nmda: ionotropic glutamate receptors

57 LTP Schaffer collateral CA1

58 LTP Schaffer collateral CA1 CRE: camp response element CREB: CAMP response element binding protein

59 LTP Schaffer collateral

60 Functional neural systems Peripheral nervous system Central nervous system Somatic nervous system Somatosensory systems Motor systems Associative systems Autonomic nervous system Sympathetic nevous system Parasympathetic nervous system Enteral nervous system