Ca in short-term plasticity - created from Mind Map

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SHORT-TERM DEPRESSION

depletion of the readily releasable pool (RRP)

reduced Ca entry

light-induced uncaging of Ca2+

remaining vesicles

vesicles- near or far from Ca Channels

changes in action potential waveform

feedback inhibition by metabotropic autoreceptors

inactivation of Ca2+ channels

Borst and Sakmann (1999)

von Gersdorff et al (1997)

CaM inhibitors

transfected SCG neuron synapses- role of CBD

auxiliary CaVβ subunits

Xu and Wu (2005)

Mochida et al (2008)

Xie et al (2007)

Attached Study Aids

Note - Short-term synaptic plasticity

SHORT-TERM FACILITATION

residual Ca2+

Ca2+ entry

effector mechanisms

1. saturation of local Ca2+ buffers, such as calbindin-D28k and parvalbumin

2. residual Ca2+ binds to a Ca2+ sensor other than that for exocytosis and activates it to increase the probability of release

Muller et al (2007)

Whole-cell recordings

parvalbumin knockouts

Reviewed by Burgoyne and Weiss (2001)

see Ca sensors

Inchauspe et al (2004; 2007)

account for only half of facilitation

α1 subunit-deficient knock-out mice

facilitation of presynaptic Ca2+ current and synaptic facilitation are lost

quantitative comparisons- Muller et al (2008)

Attached Study Aids

Note - Short-term synaptic plasticity

SENSOR PROTEINS

CaM

CaBP1

VILIP-2

NCS-1

increase inactivation, decrease facilitation

Leal et al (2012)

IM motif and CBD mutations

Co-expression

CaBP1

VILIP-2

Expression of CaV2.1 with CaBP1

CaBP1 + mutant CaV2.1-of CaS-binding sites

CaBP1 showed paired pulse depression

Coexpression of CaBP1 does not further reduce facilitation of synapses expressing the mutant CaV2.1I

facilitation of CaV2.1 channels by CaBP1 occures via CaS proteins interacting with the IM and CBD domains

Expression of CaV2.1 with VILIP-2

VILIP-2 + CaV2.1I mutant of CaS-Binding Sites

synaptic facilitation similar to controls

Contradict previous studies in transfected cells

So, raised external Ca2+ to enhance PoR and synaptic depression

Why?

high level of basal synaptic facilitation may occlude effects of VILIP-2

Lautermilch et al (2005)

decrease inactivation, increase facilitation

synapses expressing VILIP-2 show significantly more facilitation and significantly less depression

Coexpression of VILIP-2 has no effect on depression or facilitation

increase facilitation, decrease inactivation

VILIP-2 uses a complex set of interactions of three of its domains with the IM and CBD motifs in regulation of CaV2.1 channels

increases presynaptic facilitation at the calyx of Held by accelerating activation of P/Q-type Ca2+ currents

expression of NCS-1 enhances synaptic transmission

Regulation of Presynaptic Ca2+ Channels by Ca2+ and CaM

facilitation and inactivation relies of CaM

Facilitation

inactivation

mutations

C-terminal and IM mortif

Lee et al (1999; 2003)

mutations

N-terminal and CBD

Attached Study Aids

Note - Short-term synaptic plasticity

General

CaV

Presynaptic Ca current

Neurotransmitter release:

presynaptic CaV2

CaV1

subunits

binds Ca2+ sensor protein calmodulin (CaM)2

induces facilitation and inactivation of CaV2.1 channel

α1

β

γ

α2δ

pore

voltage sensors

gating apparatus

channel function

enhance cell-surface expression of α1

enhance cell-surface expression of α1 subunits

important for Ca entry and exocytosis in active zones

initiates exocytosis

release probability

Vesicle fusion and exocytosis depends on -SNARE, SNAP-25, Munc18

synchronous (phasic)

asynchronous (tonic)

low-probability spontaneous (miniature) release

presynaptic Ca2+ current

Ca2+ sensor synaptotagmin

residual Ca2

Ca2+ sensor Doc2

fluctuations in resting Ca2+

Superior cervical ganglion (SCG) neurons

voltage-gated Ca channels

a subfamily that regulates synaptic transmission

to a site in their C-terminal domain

in response to repetitive stimuli

can cause facilitation and depression of synaptic transmission

The intracellular β subunit is a hydrophilic protein

having four transmembrane segments is a component of skeletal muscle Ca2+ channels

which binds to a modified IQ-like domain (IM motif) and a downstream CaM-binding domain (CBD)

Ca2+ causes facilitation through interaction of the C-terminal lobe of CaM with the IM motif, whereas global Ca2+ causes inactivation of CaV2.1 channels by binding of the N-terminal lobe of CaM to the CBD

Ca2+ binding to CaM prebound to CaV2.1 channels may induce two sequential conformational changes, which in turn induce facilitation and inactivation

short-term facilitation is caused by residual Ca2+that builds up from action potentials

The release probability of a single synaptic vesicle increases with the number of Ca2+channels at the active zone

A primed SNARE complex requires the Ca2+-binding protein synaptotagmin, which provides rapid Ca2+-dependent regulation of exocytosis

Binding of SNARE proteins to the synaptic protein interaction (termed synprint) site (Fig. 2A) regulates expression, localization, and function of CaV2 channels

Synchronous release driven by precisely timed presynaptic Ca2+ current results in fast postsynaptic responses

Slower asynchronous release results from residual Ca2+ remaining in the terminal after an action potential

Spontaneous release results from fluctuations in resting Ca2+ concentrations or from Ca2+ release from internal stores

reduced by mutations in C-terminal EF-hands of CaM and by complementary mutations in the IM motif of CaV2.1 channels

in the N-terminal lobe of CaM and by deletion of the CBD of CaV2.1 channels

proposed mechanisms

These Ca2+ buffers are partially saturated by residual Ca2+, resulting in an additional Ca2+ increase during subsequent action potentials

Unlike Ca2+ buffers, Ca2+ sensor proteins bind Ca2+ and undergo a conformational change to regulate targets

Activation of a Ca2+sensor protein could increase Ca2+ entry and thereby enhance neurotransmitter release according to the power law or could directly modulate exocytosis

Ca2+ entry through CaV2.1 channels is necessary for synaptic facilitation at the calyx of Held

Increased Ca2+ entry could result from Ca2+-dependent increase in Ca2+channel activity by facilitation, which occurs on the millisecond time scale. Alternatively, Ca2+ channel density at the active zone could be increased, which increases synaptic strength, but there is no evidence to date that Ca2+ channels can be inserted into active zones on the millisecond time scale.

studied the role of mobile endogenous presynaptic Ca2+buffer(s) in modulating paired-pulse facilitation at calyx of Held using presynaptic whole cell recordings

The fast [Ca2+]i decay was restored by adding the slow Ca2+ buffer EGTA (50–100 μM) or parvalbumin (100 μM), a Ca2+-binding protein

the decay of [Ca2+]i and facilitation was slowed approximately twofold compared with wild-type mice

After prolonged stimulation, depletion of the readily releasable pool can result from physical depletion of the total pool of synaptic vesicles observed in electron microscopy at neuromuscular and ganglionic synapses

At the calyx of Held, even after complete depletion of the readily releasable pool of vesicles by repetitive stimulation, substantial neurotransmitter release can be elicited by light-induced uncaging of Ca2+ simultaneously throughout the nerve terminal

Remarkably, the remaining synaptic vesicles respond as rapidly as those recruited by action potentials and have similar sensitivity to Ca2+

Thus, depletion of the readily releasable pool by repeated action potentials reflects selective depletion of docked vesicles near functionally active Ca2+ channels, leaving other distant docked vesicles ready to be released with normal sensitivity by the uncaging of Ca2+ near them

has a small contribution

Ca2+-dependent inactivation of the presynaptic P/Q-type current correlates with the rapid phase of synaptic depression

partially relieve inactivation of the presynaptic Ca2+ current and reduce synaptic depression

Deletion of the CBD in the C terminus of transfected CaV2.1 channels, which blocks inactivation of P/Q-type Ca2+ currents, reduced paired-pulse depression and rapid synaptic depression during trains

>> CaM binding to the CBD induces inactivation of presynaptic CaV2.1 channels, which in turn causes rapid synaptic depression evoked by physiological activity patterns

Important in inactivation of Ca channels-

Expression of CaVβ2a in cultured neurons favors synaptic depression, whereas expression of CaVβ4a favors facilitation

calmodulin- CaM belongs to a superfamily of CaS (Ca2+ sensor) proteins

Ca2+-binding protein-1

It is co-localized with presynaptic CaV2.1 channels and binds to the CBD of the CaV2.1 α1 subunit

Visinin-like protein-2

has complementary regulatory effects to CaBP1- opposite effect to CaBP1

neuronal Ca2+ sensor-1

The evidence suggests that residual Ca2+ facilitates the activity of CaV2.1 channels via NCS-1.

causes rapid CaV2.1 inactivation in a Ca2+-independent manner, and it does not support CaV2.1 facilitation

it increases CaV2.1 facilitation

but inhibits CaV2.1 inactivation

CaBP1 and VILIP-2 to fine-tune short-term synaptic plasticity by regulation of CaV2.1 channels has been shown directly by expression of wild-type and mutant CaV2.1 channels with CaS proteins in SCG neurons

Expression of CaV2.1 channels with CaBP1, which enhances inactivation of CaV2.1 currents, causes loss of synaptic facilitation and enhanced synaptic depression in SCG neurons

We expressed CaV2.1 channels and CaBP1 or VILIP-2 by injecting cDNA into an identified SCG neuron, and we recorded excitatory postsynaptic potentials (EPSPs) from a neighboring synaptically connected but untransfected neuron

Expression of CaV2.1 with VILIP-2, which enhances facilitation of CaV2.1 currents, causes reduced synaptic depression and enhanced synaptic facilitation

suggesting that it leads to synaptic depression

synaptic facilitation followed by synaptic depression that was similar to that in control synapses

So it doesn't enhance facilitation compared to controls

lost functional effects

These results show that CaBP1 and VILIP-2 act directly on CaV2.1 channels by binding to their C-terminal regulatory site and cause push-pull regulation of the form of short-term synaptic plasticity, with CaBP1 favoring depression and VILIP-2 favoring facilitation.

coexpression of VILIP-2 with CaV2.1 channels under the conditions of our paired-pulse experiments had no effect-

overall null effect

VILIP-2 reduces inactivation of Ca2+ currents during trains of repetitive depolarizations and thereby enhances and prolongs Ca2+ current facilitation

possibly because differences in Ca2+ dynamics in presynaptic active zones versus nonneuronal cells

which means its dependent on CaS-binding sites

Ca in short-term plasticity

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