BIO304 - Midterm #2

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375 Terms

1
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What are voltage-gated calcium (CaV) channels?

Open when action potential reaches nerve terminal for calcium influx

2
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What is the function of calcium influx via CaV channels?

Interact with proteins to release presynaptic neurotransmitters from vesicles

3
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What is the function of calcium influx at NMJ?

Drives contraction of contractile filaments

4
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What is the significance of calcium in neurosignalling?

Transforms inert electrical signal of sodium & potassium to cellular processes

5
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What are 2 functions of cytoplasmic calcium?

Binds oxygen atoms + causes protein conformational changes for signaling or activating mechanical processes

6
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Where does cytoplasmic calcium bind oxygen atoms?

Carboxyl & carbonyl groups on amino acids

7
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Draw the Bohr diagram for a calcium atom.

Ca = 2, 8, 8, 2

8
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Draw the Bohr diagram for a calcium ion.

Ca2+ = [2, 8, 8]^2+

9
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What are 6 signaling / mechanical processes activated by cytoplasmic calcium?

Vesicle exocytosis, muscle contraction, activating other ion channels, changes in gene expression, apoptosis, intracellular signalling

10
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What are 3 dangers of cytoplasmic calcium?

Precipitates phosphates (CaPO4) into crystals, triggers apoptosis, cannot be chemically altered for neutralization

11
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What is phosphate precipitation as CaPO4?

Accumulates & becomes toxic

12
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What are 2 sources of phosphates for CaPO4 precipitation?

DNA + ATP

13
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What is the role of calcium in apoptosis?

Ca2+ regulatory checkpoint for programmed cell death, ex. during development

14
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What is cytoplasmic [calcium]?

Very low levels, [Ca2+]in of 10^-4 mM <<< [Ca2+]out of 1 mM (10,000 fold difference)

15
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What is cytoplasmic [calcium] vs. [potassium]?

Calcium 1.5 million fold less concentrated than potassium

16
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What is the advantage of very low cytoplasmic [calcium]?

Calcium is a good transient cytoplasmic signaling molecule

17
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What are 3 processes where cytoplasmic [calcium] increases transiently?

Neuronal excitation, muscle contraction, after a stroke by positive feedback

18
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What are 3 components of calcium-sensitive fluorescent indicators (GCaMP) for optical recording?

GFP, Ca2+ sensor protein calmodulin (CaM), M13 alpha helix of muscle protein myosin light chain kinase

19
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What is calmodulin (CaM)?

Conserved eukaryotic protein with four Ca2+ binding sites

20
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What is fluorescence of GCaMP?

Increase Ca2+ levels = increased GCaMP fluorescence

21
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  • What are 5 steps in the mechanism of GCaMP?

(1) APs cause Ca2+ influx, (2) Ca2+ activates CaM, (3) CaM binds M13 helix, (4) M13 helix pulls on GFP for conformation change, (5) increased GFP fluorescence

22
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What is the limitation of GCaMP?

Calcium influxes are long-lasting so don’t have temporal specificity to rapid action potential

23
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  • What are 6 steps in excitotoxicity after a stroke?

(1) Blood clot stops blood flow to brain region, (2) no oxygen & glucose inactivates sodium-potassium pump depolarizes Vm closer to AP threshold, (3) neurons produce barrage of AP releasing excitatory glutamate, (4) no oxygen & glucose inactivates glutamate transporters for reuptake, (5) postsynaptic neurons produce barrage of APs propagating glutamate flood, (6) excess calcium & zinc enter to trigger apoptosis

24
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How does lack of oxygen & glucose depolarize Vm?

Decreased ATP = decreased sodium-potassium pump activity = abnormally depolarized RMP = higher frequency of APs

25
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What causes neuronal death from a stroke?

Calcium-induced apoptosis rather than direct lack of oxygen & glucose

26
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What is stroke treatment for blood clots?

Thrombolytics dissolve blood clots to restore blood flow (ex. tissue plasminogen activator, tPA)

27
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What is stroke treatment for NaV channels?

Inhibitors of NaV channels reduce # of action potentials generated

28
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What is stroke treatment for glutamate receptors?

Inhibitors of glutamate receptors reduce excessive stimulation

29
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What is stroke treatment for calcium channels?

Inhibitors of calcium channels reduce intracellular calcium buildup

30
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What are 2 ways of quickly removing calcium from cytoplasm?

Cytoplasmic chelators/buffers + pumps & exchangers

31
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How do cytoplasmic chelators/buffers remove cytoplasmic calcium?

Bind free Ca2+ to remove from solution

32
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How do pumps & exchanges remove cytoplasmic calcium?

Extrude Ca2+ from cytoplasm to cell exterior or intracellular components (sarco/endoplasmic reticulum, mitochondria)

33
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What are calcium pumps?

Pump calcium out of cytoplasm

34
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What are 2 types of calcium pumps?

Plasma membrane calcium ATPase (PMCA) + sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)

35
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What is the sarcoplasmic reticulum (SR)?

ER of muscle cells storing Ca2+ for secretion during muscle contracton

36
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How are PMCA & SERCA related to sodium-potassium exchange pump?

P-type (phosphorylated intermediate)

37
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What is the structure of PMCA & SERCA?

Alpha-subunit (N & C terminus inside) with no beta-subunit

38
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What is PMCA?

Pumps out 1 Ca2+ ion out of cell per cycle via hydrolysis of single ATP molecule

39
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What are 4 human PMCA alpha genes?

Alpha 1-4 (brain/ubiquitous, brain & muscle, brain & muscle, broad distribution)

40
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What are human PMCA alpha1 mutants?

Lethal

41
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What are human PMCA alpha 2 mutants?

Hearing loss & balance

42
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What are human PMCA alpha 4 mutants?

Male infertility

43
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What is PMCA in the human protein atlas?

ATPB1 to 4

44
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What is SERCA?

Pumps out 2 Ca2+ ions into SR/ER per cycle via hydrolysis of single ATP molecule

45
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What are 3 human SERCA alpha genes?

Alpha 1-3 (muscle contraction, muscle contraction & neurons, non skeletal muscle but expressed in cardiomyocytes)

46
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What is SERCA in the human protein atlas?

ATP2A1 to 3

47
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What is sodium-potassium pump alpha subunit in human protein atlas?

ATP1A1 to 4

48
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What is sodium-potassium pump beta subunit in human protein atlas?

ATP1B1 to 4

49
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What is the disadvantage of PMCA & SERCA?

Sluggish at removing Ca2+, can’t keep up with rapid Ca2+ influx from action potential

50
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Where is SERCA highly expressed?

SR for efficient removal of cytoplasmic Ca2+ & restoration of SR Ca2+ stores

51
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Where is PMCA sparsely expressed?

Cell membrane so only good at maintaining low cytoplasmic Ca2+ levels when neuron not highly active

52
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What are calcium exchangers?

Remove cytoplasmic Ca2+ more efficiently than pumps

53
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What is the mechanism of calcium exchangers?

Secondary active transport rather than ATP hydrolysis

54
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What is secondary active transport?

Consume energy from existing [ion] gradients to move desired ions “uphill” against their gradients

55
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What are 2 calcium ion exchangers?

NCX + NCKX

56
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What are 2 names for NCX?

Na+/Ca2+ exchanger + sodium-calcium antiporter

57
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What is NCX?

1 Ca2+ out for 3 Na+ in, thus can depolarize Vm

58
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What is the abundance of NCX?

Most widely distributed sodium-calcium exchanger

59
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Why can NCX operate in reverse?

Not electrically neutral as both Na+ & Ca2+ have inward gradient

60
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What determines the direction of NCX?

Whether Na+ or Ca2+ experiences strongest inward pull (of greater amplitude)

61
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What determines inward pull of Na+ & Ca2+ in NCX?

Net ion charge x driving force

62
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What is equilibrium potential of sodium (ENa)?

+68 mV

63
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What is equilibrium potential of calcium (ECa)?

+124 mV

64
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What is the net charge of sodium for NCX?

+3

65
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What is the net charge of calcium for NCX?

+2

66
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When is Na+ pulled in & Ca2+ extruded by NCX?

| 3(Vm - ENa) | > | 2(Vm - ECa) | … near RMP (study lec 5-2 slide 19)

67
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When is Ca2+ pulled in & Na+ extruded by NCX?

| 3(Vm - ENa) | < | 2(Vm - ECa) | … at depolarized potentials (study lec 5-2 slide 19)

68
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What is NCX during a stroke?

Depolarization of Vm contributes to toxic Ca2+ influx

69
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What are calcium exchangers as revolving doors?

Whichever ion pushes on door stronger gets in while other ion gets pushed out

70
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What is NCKX (Na+/Ca2+/K+ exchanger)?

4 Na+ in & 1 K+ out for 1 Ca2+ out

71
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What is the advantage of NCKX over NCX?

Removes cytosolic Ca2 more efficiently

72
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What is the equation determining direction of NCKX?

| 4(Vm - ENa) - 1(Vm - EK) | vs. | 2(Vm - ECa) | … not electrically neutral just like NCX

73
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What is the equilibrium potential for potassium (Ek)?

-90 mV

74
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What is the direction of NCKX?

K+ & Na+ wins except at unrealistically high depolarization so no reversal

75
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Why did NCX evolve if NCKX is more efficient at removing Ca2+?

NCX needs less energy so is effective most of the time besides rare stroke-like condition

76
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What is the structure of NCX?

Transmembrane domain (9 transmembrane segments with N-terminus outside & C-terminus inside) + cytosolic domain (loop inside between 5th-6th segment)

77
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What are 3 human NCX genes?

NCX1-3 (muscle, brain, brain)

78
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What is NCX in the human protein atlas?

SLC8A1 to 3

79
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What technology was used to solve structures of NCX proteins?

Cryo-EM > X-ray crystallography at solving structures of large proteins like pumps

80
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What is AlphaFold?

Program that can predict protein structure from 1’ structure, verified experimentally

81
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What is the structure of NCKX?

Transmembrane domain (11 transmembrane segments with N-terminus inside & C-terminus outside) + cytosolic domain (loop inside between 5th & 6th segment)

82
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What is cleavage of NCKX?

N-terminal transmembrane segment cleaved

83
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What are 5 human NCKX genes?

NCKX1-5 (retina, retina & brain, brain & smooth muscle, brain & smooth muscle, not expressed at membrane)

84
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What is polymorphism of NCKX5?

Associated with white skin in individuals from Europe & Asia so might regulate Ca2+ in melanosomes

85
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What is NCKX in the human protein atlas?

SLC24A1 to 5

86
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What is gene duplication of calcium exchangers?

Gene in different cell types evolved specialized functions

87
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What is [Cl-] in immature neurons & almost all other cells?

[Cl-]in ~ [Cl-]out

88
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What is [Cl-] in mature neurons?

Actively extrude Cl- from cytoplasm so [Cl-]out >> [Cl-]in

89
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What is the equilibrium potential of potassium (Ek)?

-74 mV

90
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What is the equilibrium potential of sodium (ENa)?

+54mV

91
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What is resting membrane potential (RMP)?

-60 mV

92
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What is equilibrium potential of chloride (ECl) in immature neurons?

-5.6 (-6) mV with [100 mM]out vs. [80 mM]in

93
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How does Cl- influence Vm in immature neurons?

Pulls Vm towards ENa by trying to depolarize Vm (more depolarized than Vm)

94
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What is equilibrium potential of chloride (ECl) in mature neurons?

-74.9 mV (-75 mV) with [100 mM]out & [5 mM]in

95
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How does Cl- influence Vm in mature neurons?

Pulls Vm towards Ek by trying to hyperpolarize Vm (more hyperpolarized than Vm)

96
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What is the neurotransmitter glycine?

Excitatory neurotransmitter that activates postsynaptic Cl- channels (glycine receptors)

97
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What was Kakazhu et al.’s study?

Developmental switch of Cl- channels in mice superior olive neurons

98
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What was postnatal day 0 (P0) in Kakazu et al.?

Glycine caused depolarization of Vm

99
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What was P15 in Kakazu et al.?

Glycine caused pronounced hyperpolarization of Vm that ceased action potentials

100
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What was the Vm graph for P15 in Kakazu et. al?

Adding glycine ceased action potentials while removing glycine returned action potentials