Calcium signaling plays a key role in many neuronal functions. It is involved in synaptic transmission, where calcium influx triggers neurotransmitter release from presynaptic terminals. Calcium also regulates neuronal development by specifying neurotransmitter phenotypes in developing neurons. Dysregulation of calcium homeostasis can lead to neurodegeneration or diseases associated with calcium channel defects. Many neurological disorders like Alzheimer's, Parkinson's, and Huntington's disease involve calcium dyshomeostasis.

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Neuroscience, Dale Purves 3rd edition

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Divalent 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;

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Acts 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.

5. Calcium in Synaptic Transmission
 The 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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7. Transmitter Release Is Triggered by Calcium Influx
Adapted from Katz and Miledi ; 1967
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8. Evidence that a rise in presynaptic Ca2+ concentration triggers
transmitter release from presynaptic terminals.
AfterAdleret.al,1991
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9. Transmitter Release Is Triggered by Calcium Influx
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Neuroscience, Dale Purves, 3rd edition;

10. Transmitter Release Is Triggered by Calcium Influx
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Neuroscience, Dale Purves, 3rd edition;
Principles of Neural Science, Kandel, 5th edition

11. Transmitter Release Is Triggered by Calcium Influx
C2A domain C2B domain
3 Ca2+
2 Ca2+
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Neuroscience, Dale Purves, 3rd edition; Principles of Neural Science, Kandel, 5th
edition; Cold Spring Harb Perspect Biol 2012;4:a011353

12. Transmitter Release Is Triggered by Calcium Influx
C2A domain C2B domain
3 Ca2+
2 Ca2+
12
Neuroscience, Dale Purves, 3rd edition; Principles of Neural Science, Kandel, 5th
edition; Cold Spring Harb Perspect Biol 2012;4:a011353

13. Calcium in Learning and Memory
 Memory:
- Implicit
- Explicit
 Habituation and Sensitisation
 Long term potentiation – explicit memory storage in hippocampus
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14. Calcium in Learning and Memory(contd)
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Principles of Neural Science, Kandel – 5th

15. Calcium in Learning and Memory(contd)
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Principles of Neural Science, Kandel – 5th

16. Calcium in Learning and Memory(contd)
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Principles of Neural Science, Kandel – 5th

17. Calcium in Neuronal Developement
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 Calcium-mediated specification of neurotransmitter phenotype
Cold Spring Harb Perspect Biol 2011;3:a004259

18. Calcium-mediated specification of neurotransmitter phenotype:
 Prior to synaptogenesis a transient and spontaneous calcium activity is
recorded
 Xenopus 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
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Cold Spring Harb Perspect Biol 2011;3:a004259

19. Calcium-mediated specification of neurotransmitter phenotype:
 Prior to synaptogenesis a transient and spontaneous calcium activity is
recorded
 Xenopus 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.
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Cold Spring Harb Perspect Biol 2011;3:a004259

20. Calcium-mediated specification of neurotransmitter phenotype:
Mechanism:
 Intracellular Ca2+ release is needed for this differentiation
 Seems to occur via a frequency-mediated mechanism
regulates gene
expression? 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.
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Cold Spring Harb Perspect Biol 2011;3:a004259
specific frequency for specific NT?

21. 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.
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Cold Spring Harb Perspect Biol 2011;3:a004259

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Cold 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)

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Cold 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)

24. Calcium and cAMP in Axonal Guidance
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Neuron 74, 490–503, May 10, 2012 ©2012 Elsevier Inc.
 Dependence of attraction versus repulsion on calcium levels;
 cAMP mediated directional switching;

25. Calcium and cAMP in Axonal Guidance
25
Neuron 74, 490–503, 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;

26. Calcium and cAMP in Axonal Guidance
26
Neuron 74, 490–503, May 10, 2012 ©2012 Elsevier Inc.
 Signal transduction of CaMKII/CaN:
Higher Ca-CaM
affinity
Lower Ca-CaM
affinity

27. Calcium and cAMP in Axonal Guidance
27
Neuron 74, 490–503, May 10, 2012 ©2012 Elsevier Inc.
 Signal transduction of CaMKII/CaN:
Higher Ca-CaM
affinity
inhibits
inhibitor
inhibitor
Lower Ca-CaM
affinity

28. Calcium and cAMP in Axonal Guidance
28
Neuron 74, 490–503, May 10, 2012 ©2012 Elsevier Inc.
 Signal transduction of CaMKII/CaN:
Higher Ca-CaM
affinity
Lower Ca-CaM
affinity
inhibits
high
inhibitor
inhibitor

29. Calcium and cAMP in Axonal Guidance
29
Neuron 74, 490–503, May 10, 2012 ©2012 Elsevier Inc.
 Signal transduction of CaMKII/CaN:
Higher Ca-CaM
affinity
Lower Ca-CaM
affinity
inhibits
inhibitor
activates
high
inhibitor
x

30. Calcium and cAMP in Axonal Guidance
30
Neuron 74, 490–503, May 10, 2012 ©2012 Elsevier Inc.
 Signal transduction of CaMKII/CaN:
Higher Ca-CaM
affinity
inhibits
inhibitor
inhibitor
Lower Ca-CaM
affinity
low

31. Calcium and cAMP in Axonal Guidance
31
Neuron 74, 490–503, May 10, 2012 ©2012 Elsevier Inc.
 Signal transduction of CaMKII/CaN:
Higher Ca-CaM
affinity
inhibits
inhibitor
inhibitor
Lower Ca-CaM
affinity
low
x

32. Calcium in Excitotoxicity – The Brain’s 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
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Neuroscience, M.F.Bear – 2nd edition
X

33. Calcium in Excitotoxicity – The Brain’s 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
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34. Calcium in Excitotoxicity – The Brain’s 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 membrane
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35. Diseases of calcium channel defect - Channelopathies
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Structure of L-type voltage gated calcium channel

36. Diseases in calcium channel defect - Channelopathies
 10 different genes encode the α1-subunit of the P/Q type calcium channel
protein (the CACNA genes);
 CACNA1A gene (α1A-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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Alzheimer’s Disease

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Alzheimer’s Disease
Affects tau-
phosphorylation and
APP processing
Aβ oligomers form Ca2+
conducting pores and
generate ROS
Aβ 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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Parkinson’s Disease Alzheimer’s Disease
Affects tau-
phosphorylation and
APP processing
Aβ oligomers form Ca2+
conducting pores and
generate ROS
Aβ 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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Parkinson’s 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
α-synuclein potentiates Ca-
dyshomeostasis
DA depletion
overactivates Glu
projections – alter of
NMDAR function
Alzheimer’s Disease
Affects tau-
phosphorylation and
APP processing
Aβ oligomers form Ca2+
conducting pores and
generate ROS
Aβ 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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Huntington’s DiseaseParkinson’s 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
α-synuclein potentiates Ca-
dyshomeostasis
DA depletion
overactivates Glu
projections – alter of
NMDAR function
Alzheimer’s Disease
Affects tau-
phosphorylation and
APP processing
Aβ oligomers form Ca2+
conducting pores and
generate ROS
Aβ 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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MSN neurons express
high levels of mGluR5
acting via IP3R
Huntingtin(Ht) binds to
IP3R and sensitises it
Ht interferes NR2B of
NMDA-R binding to
PSD-95 -
hypersensitivity
Ca-overload and
excitotoxocity
Opening of MPTP –
mitochondrial death
Huntington’s DiseaseParkinson’s 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
α-synuclein potentiates Ca-
dyshomeostasis
DA depletion
overactivates Glu
projections – alter of
NMDAR function
Alzheimer’s Disease
Affects tau-
phosphorylation and
APP processing
Aβ oligomers form Ca2+
conducting pores and
generate ROS
Aβ 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

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Amyotrophic Lateral Sclerosis
Spinal 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 Sclerosis
Spinal 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 glia
Feedback stimulation of
GABA and rebound AP burst
Activates at
hyperpolarised state - AP
Amyotrophic Lateral Sclerosis
Spinal 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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SchiczophreniaEpilepsy
Neurons in the seizure
focus exhibit Paroxysmal
Depolarising Shift (PDS)
Sustained excitibility –
TCa of thalamic relay
neurons
K+ accumulation and Ca-
wave in glia
Feedback stimulation of
GABA and rebound AP burst
Activates at
hyperpolarised state - AP
Amyotrophic Lateral Sclerosis
Spinal 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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Alteration of Ca-
signalling due to
developmental
dysfuntions of NTs
RGS4 (inhibits Gq
induced Ca-release) is
downregulated in
temporal cortex
GAP43 (absorbs free CaM
and prevents Ca-binding)
increases in cortex and
hippocampus
Expression of CaBP
decreases in cortex
NMDAR hypofunction
and deficit
SchiczophreniaEpilepsy
Neurons in the seizure
focus exhibit Paroxysmal
Depolarising Shift (PDS)
Sustained excitibility –
TCa of thalamic relay
neurons
K+ accumulation and Ca-
wave in glia
Feedback stimulation of
GABA and rebound AP burst
Activates at
hyperpolarised state - AP
Amyotrophic Lateral Sclerosis
Spinal 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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