Download - Calcium in Neuronal Homeostasis
Calcium in Neuronal Homeostasis
Calcium in Neuronal HomeostasisSatadru DeM.Phil 1st yearDepartment of NeurophysiologyNational Institute of Mental Health And Neuro SciencesBangalore1
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Neuroscience, Dale Purves 3rd edition
3Divalent Ca2+ is the most common signal transduction element in the cells, ranging from bacteria to specialised neurons;
Implicated in several physiological processes:Excitation-contraction coupling of -Skeletal muscle -Smooth muscle, and -Cardiac muscle; Endocrine signalling of peptide hormones; Bone Calcification; Vitamin D metabolism, etc;
Ca2+ regulation is a critical process in the biochemical machinery of a neuron
Maintains neural integrity and integrates diverse cellular functions;
4Acts as a pluripotent signal for many neuronal functions:
Synaptic activity; Learning and memory consolidation; Neuronal developement;
Dysregulation of Ca2+ homeostasis may lead to:
Excitotoxicity; Channelopathies; Neurodenegeration.
Calcium in Synaptic TransmissionThe signalling between neurons along a specialised site of communication called a Synapse;
Synapses can be: -Electrical - Type 1 -Chemical - Type 2 The sequence of events at a synapse during neurotransmission:
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Transmitter Release Is Triggered by Calcium Influx
Adapted from Katz and Miledi ; 1967
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Evidence that a rise in presynaptic Ca2+ concentration triggerstransmitter release from presynaptic terminals.
After Adler et. al, 19918
Transmitter Release Is Triggered by Calcium Influx
9Neuroscience, Dale Purves, 3rd edition;
Transmitter Release Is Triggered by Calcium Influx
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Neuroscience, Dale Purves, 3rd edition;Principles of Neural Science, Kandel, 5th edition
Transmitter Release Is Triggered by Calcium Influx
C2A domain C2B domain3 Ca2+2 Ca2+11
Neuroscience, Dale Purves, 3rd edition; Principles of Neural Science, Kandel, 5th edition; Cold Spring Harb Perspect Biol 2012;4:a011353
Transmitter Release Is Triggered by Calcium Influx
C2A domain C2B domain3 Ca2+2 Ca2+12
Neuroscience, Dale Purves, 3rd edition; Principles of Neural Science, Kandel, 5th edition; Cold Spring Harb Perspect Biol 2012;4:a011353
Calcium in Learning and MemoryMemory: - Implicit - Explicit
Habituation and Sensitisation
Long term potentiation explicit memory storage in hippocampus
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Calcium in Learning and Memory(contd)14
Principles of Neural Science, Kandel 5th
Calcium in Learning and Memory(contd)15
Principles of Neural Science, Kandel 5th
Calcium in Learning and Memory(contd)16
Principles of Neural Science, Kandel 5th
Calcium in Neuronal Developement17
Calcium-mediated specification of neurotransmitter phenotype
Cold Spring Harb Perspect Biol 2011;3:a004259
Calcium-mediated specification of neurotransmitter phenotype:Prior to synaptogenesis a transient and spontaneous calcium activity is recordedXenopus embryonic spinal cord cells have two types of transient spontaneous activity: (Gu et al. 1994; Spitzer et al. 1994; Gu and Spitzer 1995, 1997) -Calcium spikes -Calcium waves
18Cold Spring Harb Perspect Biol 2011;3:a004259
Calcium-mediated specification of neurotransmitter phenotype:Prior to synaptogenesis a transient and spontaneous calcium activity is recordedXenopus embryonic spinal cord cells have two types of transient spontaneous activity: (Gu et al. 1994; Spitzer et al. 1994; Gu and Spitzer 1995, 1997) -Calcium spikes -Calcium waves
How do they determine the neurotransmitter phenotype? Embryonic Xenopus neurons showed that Ca-spikes are necessary and sufficient for specific NT expression in the spinal neurons.19Cold Spring Harb Perspect Biol 2011;3:a004259
Calcium-mediated specification of neurotransmitter phenotype:Mechanism: Intracellular Ca2+ release is needed for this differentiation Seems to occur via a frequency-mediated mechanism
regulates geneexpression? Different frequency needed for each subtype?
Before synaptogenesis cells showing low spike frequency express glutamate and with a gradually increasing spike frequency expressed Ach
Cells showing high spike frequency expressed inhibitory neurotransmitters, like GABA.
20Cold Spring Harb Perspect Biol 2011;3:a004259specific frequency for specific NT?
Calcium-mediated specification of neurotransmitter phenotype:Homeostatic relation between Ca-signalling and NT expression can be established: (Borodinsky et al. 2004)
Injection of Na-channel Injection of Kir transcript transcript at 2-celled stage
global increase in Ca- decrease in Ca-spiking spiking activity
expression expression of Glu, Ach; of Glu, Ach; expression of GABA, Gly. expression of GABA, Gly.
21Cold Spring Harb Perspect Biol 2011;3:a004259
22Cold Spring Harb Perspect Biol 2011;3:a004259tlx3 homeobox gene mediates the activity dependant fate of GABA and Glu expression(Marek et al. 2010; Cheng et al. 2004,2005)
23Cold Spring Harb Perspect Biol 2011;3:a004259
tlx3 homeobox gene mediates the activity dependant fate of GABA and Glu expression(Marek et al. 2010; Cheng et al. 2004,2005)
Calcium and cAMP in Axonal Guidance24Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc.
Dependence of attraction versus repulsion on calcium levels; cAMP mediated directional switching;
Calcium and cAMP in Axonal Guidance25Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc.
Blocking Ca-entry can turn a attractive cue to a repellant cue (Hong et al. 2000)
Effectors of Ca-CaM complex in growth cone turning : CaMKII and Calcineurin; CaMKII attracts; CaN repels;
Baseline calcium level is important is mediating response interaction of baseline level and influx/ IC release;
When baseline level is reduced, small or large local Ca2+ increase lowers CaMKII:CaN ration and causes repulsion;
Calcium and cAMP in Axonal Guidance26Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc. Signal transduction of CaMKII/CaN:
Higher Ca-CaMaffinityLower Ca-CaMaffinity
Calcium and cAMP in Axonal Guidance27Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc. Signal transduction of CaMKII/CaN:
Higher Ca-CaMaffinityinhibitsinhibitorinhibitor
Lower Ca-CaMaffinity
Calcium and cAMP in Axonal Guidance28Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc. Signal transduction of CaMKII/CaN:
Higher Ca-CaMaffinityLower Ca-CaMaffinityinhibitshigh
inhibitorinhibitor
Calcium and cAMP in Axonal Guidance29Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc. Signal transduction of CaMKII/CaN:
Higher Ca-CaMaffinityLower Ca-CaMaffinityinhibitsinhibitoractivateshigh
inhibitor x
Calcium and cAMP in Axonal Guidance30Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc. Signal transduction of CaMKII/CaN:
Higher Ca-CaMaffinityinhibitsinhibitorinhibitor
Lower Ca-CaMaffinitylow
Calcium and cAMP in Axonal Guidance31Neuron 74, 490503, May 10, 2012 2012 Elsevier Inc. Signal transduction of CaMKII/CaN:
Higher Ca-CaMaffinityinhibitsinhibitorinhibitor
Lower Ca-CaMaffinitylow x
Calcium in Excitotoxicity The Brains Exciting Poisons Neurons devoid of O2 (hypoxia, cardiac arrest, injury) ATP Depolarisation Presynaptic release of Glutamate Increased postsynaptic [Ca2+] by activation of GluRs Cyclical release of Glutamate Overexcitement of neurons and enhanced influx of Na+, K+, Ca2+ Acute effect Chronic Effect
32Neuroscience, M.F.Bear 2nd edition X
Calcium in Excitotoxicity The Brains Exciting Poisons Acute effect Chronic Effect Na+ and K+ influx Opening of VGCC/NMDAR Secondary influx of Cl- and H2O Influx of EC Ca2+ and release from IC stores Cell swelling and death Ca2+ induced activation of degrading enzymes 33
Calcium in Excitotoxicity The Brains Exciting Poisons Acute effect Chronic Effect Na+ and K+ influx Opening of VGCC/NMDAR Secondary influx of Cl- and H2O Influx of EC Ca2+ and release from IC stores Cell swelling and death Ca2+ induced activation of degrading enzymes Calpain 1 degrades the cellular Phospholipase-C Calcineurin cytoskeleton and Xanthine oxidase generate ROS Apoptosis
Perioxidative degradation of membrane34
Diseases of calcium channel defect - Channelopathies
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Structure of L-type voltage gated calcium channel
Diseases in calcium channel defect - Channelopathies 10 different genes encode the 1-subunit of the P/Q type calcium channel protein (the CACNA genes); CACNA1A gene (1A-subunit) mutation on chromosome 19p13 is implicated in
Familial Hemiplegic Episodic Ataxia 2 Spinocerebellar Idiopathic Gen Migraine(FHM) (EA2) Ataxia-6(SCA6) -eralised Epilepsy
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Alzheimers Disease
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Alzheimers DiseaseAffects tau-phosphorylation and APP processing
A oligomers form Ca2+ conducting pores and generate ROS
A impairs NMDAR signalling and no. of NMDAR
Mutant PS1/PS2 enhance Ca-release from ER stores alter synaptic activty of hippocampus
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Parkinsons Disease
Alzheimers DiseaseAffects tau-phosphorylation and APP processing
A oligomers form Ca2+ conducting pores and generate ROS
A impairs NMDAR signalling and no. of NMDAR
Mutant PS1/PS2 enhance Ca-release from ER stores alter synaptic activty of hippocampus
41Ca2+
Parkinsons Disease
Dramatic reduction in Calbindin D28k mRNA in SNpc, hippocampus of PD brains
L type VGCC open for longer duration in aged neurons Ca overload
Inc. basal metabolism of SNpc and ROS generation-synuclein potentiates Ca-dyshomeostasis
DA depletion overactivates Glu projections alter of NMDAR function
Alzheimers DiseaseAffects tau-phosphorylation and APP processing
A oligomers form Ca2+ conducting pores and generate ROS
A impairs NMDAR signalling and no. of NMDAR
Mutant PS1/PS2 enhance Ca-release from ER stores alter synaptic activty of hippocampus
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Huntingtons Disease
Parkinsons DiseaseDramatic reduction in Calbindin D28k mRNA in SNpc, hippocampus of PD brains
L type VGCC open for longer duration in aged neurons Ca overload
Inc. basal metabolism of SNpc and ROS generation-synuclein potentiates Ca-dyshomeostasis
DA depletion overactivates Glu projections alter of NMDAR function
Alzheimers DiseaseAffects tau-phosphorylation and APP processing
A oligomers form Ca2+ conducting pores and generate ROS
A impairs NMDAR signalling and no. of NMDAR
Mutant PS1/PS2 enhance Ca-release from ER stores alter synaptic activty of hippocampus
43Ca2+
MSN neurons express high levels of mGluR5 acting via IP3R
Huntingtin(Ht) binds to IP3R and sensitises itHt interferes NR2B of NMDA-R binding to PSD-95 - hypersensitivity
Ca-overload and excitotoxocity
Opening of MPTP mitochondrial deathHuntingtons Disease
Parkinsons DiseaseDramatic reduction in Calbindin D28k mRNA in SNpc, hippocampus of PD brains
L type VGCC open for longer duration in aged neurons Ca overload
Inc. basal metabolism of SNpc and ROS generation-synuclein potentiates Ca-dyshomeostasis
DA depletion overactivates Glu projections alter of NMDAR function
Alzheimers DiseaseAffects tau-phosphorylation and APP processing
A oligomers form Ca2+ conducting pores and generate ROS
A impairs NMDAR signalling and no. of NMDAR
Mutant PS1/PS2 enhance Ca-release from ER stores alter synaptic activty of hippocampus
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Amyotrophic Lateral Sclerosis
45Ca2+
Amyotrophic Lateral SclerosisSpinal MN show relative lack of parvalbumin and Calbindin D28k lost early
Express AMPA-R lacking GluR2 Ca permeability and excitotoxicity
ETC impairment (complex I and IV) and mitochondrial death
Ca overload linked to SOD1 aggregation
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Epilepsy
Amyotrophic Lateral SclerosisSpinal MN show relative lack of parvalbumin and Calbindin D28k lost early
Express AMPA-R lacking GluR2 Ca permeability and excitotoxicity
ETC impairment (complex I and IV) and mitochondrial death
Ca overload linked to SOD1 aggregation
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Epilepsy
Neurons in the seizure focus exhibit Paroxysmal Depolarising Shift (PDS)
Sustained excitibility TCa of thalamic relay neurons
K+ accumulation and Ca-wave in gliaFeedback stimulation of GABA and rebound AP burst
Activates at hyperpolarised state - AP
Amyotrophic Lateral SclerosisSpinal MN show relative lack of parvalbumin and Calbindin D28k lost early
Express AMPA-R lacking GluR2 Ca permeability and excitotoxicity
ETC impairment (complex I and IV) and mitochondrial death
Ca overload linked to SOD1 aggregation
48Ca2+
Schiczophrenia
EpilepsyNeurons in the seizure focus exhibit Paroxysmal Depolarising Shift (PDS)
Sustained excitibility TCa of thalamic relay neurons
K+ accumulation and Ca-wave in gliaFeedback stimulation of GABA and rebound AP burst
Activates at hyperpolarised state - AP
Amyotrophic Lateral SclerosisSpinal MN show relative lack of parvalbumin and Calbindin D28k lost early
Express AMPA-R lacking GluR2 Ca permeability and excitotoxicity
ETC impairment (complex I and IV) and mitochondrial death
Ca overload linked to SOD1 aggregation
49Ca2+
Alteration of Ca-signalling due to developmental dysfuntions of NTs
RGS4 (inhibits Gq induced Ca-release) is downregulated in temporal cortexGAP43 (absorbs free CaM and prevents Ca-binding) increases in cortex and hippocampus
Expression of CaBP decreases in cortex
NMDAR hypofunction and deficitSchiczophrenia
EpilepsyNeurons in the seizure focus exhibit Paroxysmal Depolarising Shift (PDS)
Sustained excitibility TCa of thalamic relay neurons
K+ accumulation and Ca-wave in gliaFeedback stimulation of GABA and rebound AP burst
Activates at hyperpolarised state - AP
Amyotrophic Lateral SclerosisSpinal MN show relative lack of parvalbumin and Calbindin D28k lost early
Express AMPA-R lacking GluR2 Ca permeability and excitotoxicity
ETC impairment (complex I and IV) and mitochondrial death
Ca overload linked to SOD1 aggregation
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