Explore Cellular Neurophysiology at UCL. Dive into the intricate world of Neuronal Calcium Signaling, exploring transport mechanisms, glial cells, synapse dynamics, bioelectricity, action potentials, ion channels, and the transformative realm of optogenetics.
Neuronal Calcium Signalling
Neuronal Calcium Signalling
Calcium as a signalling molecule
o Discovery
Experient
Interested in the influence of blood constituents on heart contraction
Solution used to maintain beating hearts = saline solution
o Used distilled water added salts
When heart was submerged – quickly stopped beating
Small amounts of Ca2+ in the perfusing solution are necessary for the maintenance of a
normal heartbeat
o Unique
Different from other second messengers and signalling molecules
Not synthesised from precursors
Cannot be broken down
o Most versatile
Controls a broad and diverse range of neuronal functions
Neurotransmitter release
Membrane excitability
Synaptic plasticity
Changes in gene expression
Growth and differentiation of neurons in development
Programmed neuronal death
2+
Ca facts and numbers
o Steep electrochemical gradient in neurons
Extracellular concentration = 1-2mM
Intracellular concentration = 50-100nM
o Diffusion constant DCa depends on ion size and medium
DCa in water = 600μm2/s
DCa in cytoplasm = 200μm2/s
o Estimated to migrate no further than 0.1-0.5μm + lasts only 50μs before encountering a binding
protein
o Calcium signal
Action of neurotransmitter Ca2+ channel opening steep elevation of intracellular Ca2+
levels from 100nM to 1000nM
Generating specificity of Ca2+ signalling
Regulated at 2 levels
o Spatially
How far Ca2+ spreads within the cell
o Temporally
How long Ca2+ stays elevated in neurons
Calcium homeostasis
o Large Ca2+ concentration gradients are useful for signalling purposes
Drives signalling processes
Similar gradient found between Ca2+ concentration in intracellular organelles and cytoplasm
driving movement of Ca2+ across membrane of organelles
o Ca2+ is toxic
Activates enzymes responsible for necrosis
o Various homeostatic mechanisms in operation to maintain Ca2+ at low levels
, Neuronal Calcium Signalling
Specific stimuli / signals reach the
neuron lead to generation of Ca2+
mobilising signals in the cell act on
mechanisms (ON mechanisms) lead
to an elevation of cytoplasmic free Ca2+
concentration binds to different
target effectors leading to activation
of Ca2+-sensitive processes in the cell
Intracellular cytoplasmic Ca2+ elevation
needs to be kept short and localised –
through the action of OFF mechanisms
– which terminate the Ca2+ signal
restoring resting Ca2+ levels in resting neurons
Elements of the Ca2+ signalling toolkit
o
o Stimulus generates calcium mobilising signals
Stimuli act through a variety of membrane surface receptors – including:
GPCRs
o Lead to the activation of phospholipase C β (PLCβ)
Tyrosine receptors
o Lead to the activation of phospholipase C γ (PLCγ)
Other receptors that activate NAD/NADP pathway
o Leading to the activation of ADP ribosyl cyclase + generation of second
messengers – cADPR, NAADP, S1P
o Calcium mobilising signals act on ON mechanisms = elevate intracellular Ca 2+ levels
Second messengers result in the activation of specific receptors on the endoplasmic
reticulum – InsP3R. RYR, SCaMPER, NAADPR
Change in transmembrane voltage depolarisation of membrane potential results in
activation of voltage-gated Ca2+ channels Ca2+ influx – directly elevating intracellular Ca2+
levels
Other stimuli may act directly on ligand-gated Ca 2+ channels
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