Ca in short-term plasticity - created from Mind Map

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 AidsNote - 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 AidsNote - 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 AidsNote - 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 stimulican 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 CBDCa2+ 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 exocytosisBinding 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 targetsActivation 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 terminalRemarkably, 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 neuronsWe 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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