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Papers by karina leal|

Research paper thumbnail of Cellular/Molecular Isoform Specificity of PKC Translocation in Living Aplysia Sensory Neurons and a Role for Ca 2 �-Dependent PKC APL I in the Induction of Intermediate-Term Facilitation

Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are tw... more Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are two major phorbol ester-activated PKCs, Ca 2 �-activated PKC Apl I and Ca 2 �-independent PKC Apl II. Functional Apl II, but not Apl I, in sensory neurons is required for a form of short-term facilitation induced at sensorimotor synapses by the facilitatory transmitter serotonin (5-HT). Because PKCs are activated by translocating from the cytoplasm to the membrane, we used fluorescently tagged PKCs to determine the isoform and cell-type specificity of translocation in living Aplysia neurons. In Sf9 cells, low levels of diacylglycerol translocate Apl II, but not Apl I, which requires calcium for translocation at low concentrations of diacylglycerol. Accordingly, application of 5-HT to Aplysia sensory neurons in the absence of neuronal firing translocates Apl II, but not Apl I, consistent with the role of Apl II in short-term facilitation. This translocation is observed in sensory neurons, b...

Research paper thumbnail of Isoform Specificity of PKC Translocation in Living Aplysia Sensory Neurons and a Role for Ca2+-Dependent PKC APL I in the Induction of Intermediate-Term Facilitation

Journal of Neuroscience, 2006

Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are tw... more Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are two major phorbol ester-activated PKCs, Ca 2ϩ-activated PKC Apl I and Ca 2ϩ-independent PKC Apl II. Functional Apl II, but not Apl I, in sensory neurons is required for a form of short-term facilitation induced at sensorimotor synapses by the facilitatory transmitter serotonin (5-HT). Because PKCs are activated by translocating from the cytoplasm to the membrane, we used fluorescently tagged PKCs to determine the isoform and cell-type specificity of translocation in living Aplysia neurons. In Sf9 cells, low levels of diacylglycerol translocate Apl II, but not Apl I, which requires calcium for translocation at low concentrations of diacylglycerol. Accordingly, application of 5-HT to Aplysia sensory neurons in the absence of neuronal firing translocates Apl II, but not Apl I, consistent with the role of Apl II in short-term facilitation. This translocation is observed in sensory neurons, but not in motor neurons. Apl I translocates only if 5-HT is coupled to firing in the sensory neuron; firing alone is ineffective. Because combined 5-HT and firing are required for the induction of one type of intermediate-term facilitation at these synapses, we asked whether this form of synaptic plasticity involves activation of Apl I. We report here that dominantnegative Apl I, but not Apl II, blocks intermediate-term facilitation. Thus, different isoforms of PKC translocate under different conditions to mediate distinct types of synaptic plasticity: Ca 2ϩ-independent Apl II is involved in short-term facilitation, and Ca 2ϩ-dependent Apl I contributes to intermediate-term facilitation.

Research paper thumbnail of Fine-tuning synaptic plasticity by modulation of Ca V 2.1 channels with Ca 2+ sensor proteins

Proceedings of the National Academy of Sciences, 2012

Modulation of P/Q-type Ca 2+ currents through presynaptic voltage-gated calcium channels (Ca V 2.... more Modulation of P/Q-type Ca 2+ currents through presynaptic voltage-gated calcium channels (Ca V 2.1) by binding of Ca 2+ /calmodulin contributes to short-term synaptic plasticity. Ca 2+ -binding protein-1 (CaBP1) and Visinin-like protein-2 (VILIP-2) are neurospecific calmodulin-like Ca 2+ sensor proteins that differentially modulate Ca V 2.1 channels, but how they contribute to short-term synaptic plasticity is unknown. Here, we show that activity-dependent modulation of presynaptic Ca V 2.1 channels by CaBP1 and VILIP-2 has opposing effects on short-term synaptic plasticity in superior cervical ganglion neurons. Expression of CaBP1, which blocks Ca 2+ -dependent facilitation of P/Q-type Ca 2+ current, markedly reduced facilitation of synaptic transmission. VILIP-2, which blocks Ca 2+ -dependent inactivation of P/Q-type Ca 2+ current, reduced synaptic depression and increased facilitation under conditions of high release probability. These results demonstrate that activity-dependent ...

Research paper thumbnail of Direct enhancement of presynaptic calcium influx in presynaptic facilitation at Aplysia sensorimotor synapses

Molecular and Cellular Neuroscience, 2009

Regulation of synaptic transmission by modulation of the calcium influx that triggers transmitter... more Regulation of synaptic transmission by modulation of the calcium influx that triggers transmitter release underlies different forms of synaptic plasticity, and thus could contribute to learning. In the mollusk Aplysia, the neuromodulator serotonin (5-HT) increases evoked transmitter release from sensory neurons and thereby contributes to dishabituation and sensitization of defensive reflexes. We combined electrophysiological recording with fluorescence measurements of intracellular calcium in sensory neuron synapses in culture to test whether direct up-modulation by 5-HT of calcium influx triggered by single action potentials contributes to facilitation of transmitter release. We observe increases in a previously undescribed calcium influx that are strongly correlated with increases in the amplitude of the evoked postsynaptic potentials and which cannot be accounted for by action potential prolongation. Our results suggest that direct modulation of a presynaptic calcium conductance that controls neurotransmitter release contributes to the presynaptic facilitation that underlies a simple form of learning.

Research paper thumbnail of Calcium Channels and Short-term Synaptic Plasticity

Journal of Biological Chemistry, 2013

Voltage-gated Ca 2؉ channels in presynaptic nerve terminals initiate neurotransmitter release in ... more Voltage-gated Ca 2؉ channels in presynaptic nerve terminals initiate neurotransmitter release in response to depolarization by action potentials from the nerve axon. The strength of synaptic transmission is dependent on the third to fourth power of Ca 2؉ entry, placing the Ca 2؉ channels in a unique position for regulation of synaptic strength. Short-term synaptic plasticity regulates the strength of neurotransmission through facilitation and depression on the millisecond time scale and plays a key role in encoding information in the nervous system. Ca V 2.1 channels are the major source of Ca 2؉ entry for neurotransmission in the central nervous system. They are tightly regulated by Ca 2؉ , calmodulin, and related Ca 2؉ sensor proteins, which cause facilitation and inactivation of channel activity. Emerging evidence reviewed here points to this mode of regulation of Ca V 2.1 channels as a major contributor to short-term synaptic plasticity of neurotransmission and its diversity among synapses. Ca 2ϩ influx through voltage-gated Ca 2ϩ (termed Ca V) channels at presynaptic nerve terminals is an essential step in neurotransmission and plays a crucial role in short-term synaptic plasticity. The Ca V 2 subfamily is predominant in initiating synaptic transmission at fast conventional synapses (1-3). Multiple mechanisms modulate the function of presynaptic Ca V 2 channels and thereby regulate synaptic transmission (2, 4-6). Ca V 2 channels bind the ubiquitous Ca 2ϩ sensor protein calmodulin (CaM) 2 to a site in their C-terminal domain, which induces Ca 2ϩ-dependent facilitation and inactivation of Ca V 2.1 channel activity in response to repetitive stimuli (7-10). Facilitation and inactivation of Ca V 2 channel activity can cause facilitation and depression of synaptic transmission (11, 12). In this minireview, we focus on regulation of the presynaptic Ca V 2 channels by different calcium sensor proteins and the role of this mechanism in short-term synaptic plasticity.

Research paper thumbnail of Regulation of Active Zone Ca2+ Channels

Presynaptic Terminals, 2014

At the presynaptic active zone, Ca2+ influx through voltage-gated CaV2 channels triggers fast, sy... more At the presynaptic active zone, Ca2+ influx through voltage-gated CaV2 channels triggers fast, synchronous neurotransmitter release from synaptic vesicles. Synaptic vesicles localized to release sites are tightly coupled with presynaptic CaV2 channels whereby neurotransmitter release is proportional to the Ca2+ current, or the Ca2+ concentration, with the third or fourth power. CaV2 channel activity is regulated directly or indirectly by multiple mechanisms through protein-protein interactions, before and after synaptic vesicle exocytosis, resulting in fine-tuning of Ca2+ entry that effectively modulates basal neurotransmitter release and underlies presynaptic short-term plasticity. Presynaptic active zone proteins form a large complex, which tether CaV2 channels, dock and prime synaptic vesicles at release sites, and possess regulatory function. CaV2 channel modulation, which is upstream of synaptic vesicle exocytosis, that leads to changes in Ca2+ influx provides a powerful and efficient way to regulate synaptic transmission. In this chapter, we review progress toward understanding the cellular and molecular mechanisms that modulate the activity of Ca2+ channels at the presynaptic active zone. A remaining challenge is to understand how these processes work together to shape synaptic transmission and synaptic plasticity.

Research paper thumbnail of Cellular/Molecular Isoform Specificity of PKC Translocation in Living Aplysia Sensory Neurons and a Role for Ca 2 �-Dependent PKC APL I in the Induction of Intermediate-Term Facilitation

Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are tw... more Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are two major phorbol ester-activated PKCs, Ca 2 �-activated PKC Apl I and Ca 2 �-independent PKC Apl II. Functional Apl II, but not Apl I, in sensory neurons is required for a form of short-term facilitation induced at sensorimotor synapses by the facilitatory transmitter serotonin (5-HT). Because PKCs are activated by translocating from the cytoplasm to the membrane, we used fluorescently tagged PKCs to determine the isoform and cell-type specificity of translocation in living Aplysia neurons. In Sf9 cells, low levels of diacylglycerol translocate Apl II, but not Apl I, which requires calcium for translocation at low concentrations of diacylglycerol. Accordingly, application of 5-HT to Aplysia sensory neurons in the absence of neuronal firing translocates Apl II, but not Apl I, consistent with the role of Apl II in short-term facilitation. This translocation is observed in sensory neurons, b...

Research paper thumbnail of Isoform Specificity of PKC Translocation in Living Aplysia Sensory Neurons and a Role for Ca2+-Dependent PKC APL I in the Induction of Intermediate-Term Facilitation

Journal of Neuroscience, 2006

Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are tw... more Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are two major phorbol ester-activated PKCs, Ca 2ϩ-activated PKC Apl I and Ca 2ϩ-independent PKC Apl II. Functional Apl II, but not Apl I, in sensory neurons is required for a form of short-term facilitation induced at sensorimotor synapses by the facilitatory transmitter serotonin (5-HT). Because PKCs are activated by translocating from the cytoplasm to the membrane, we used fluorescently tagged PKCs to determine the isoform and cell-type specificity of translocation in living Aplysia neurons. In Sf9 cells, low levels of diacylglycerol translocate Apl II, but not Apl I, which requires calcium for translocation at low concentrations of diacylglycerol. Accordingly, application of 5-HT to Aplysia sensory neurons in the absence of neuronal firing translocates Apl II, but not Apl I, consistent with the role of Apl II in short-term facilitation. This translocation is observed in sensory neurons, but not in motor neurons. Apl I translocates only if 5-HT is coupled to firing in the sensory neuron; firing alone is ineffective. Because combined 5-HT and firing are required for the induction of one type of intermediate-term facilitation at these synapses, we asked whether this form of synaptic plasticity involves activation of Apl I. We report here that dominantnegative Apl I, but not Apl II, blocks intermediate-term facilitation. Thus, different isoforms of PKC translocate under different conditions to mediate distinct types of synaptic plasticity: Ca 2ϩ-independent Apl II is involved in short-term facilitation, and Ca 2ϩ-dependent Apl I contributes to intermediate-term facilitation.

Research paper thumbnail of Fine-tuning synaptic plasticity by modulation of Ca V 2.1 channels with Ca 2+ sensor proteins

Proceedings of the National Academy of Sciences, 2012

Modulation of P/Q-type Ca 2+ currents through presynaptic voltage-gated calcium channels (Ca V 2.... more Modulation of P/Q-type Ca 2+ currents through presynaptic voltage-gated calcium channels (Ca V 2.1) by binding of Ca 2+ /calmodulin contributes to short-term synaptic plasticity. Ca 2+ -binding protein-1 (CaBP1) and Visinin-like protein-2 (VILIP-2) are neurospecific calmodulin-like Ca 2+ sensor proteins that differentially modulate Ca V 2.1 channels, but how they contribute to short-term synaptic plasticity is unknown. Here, we show that activity-dependent modulation of presynaptic Ca V 2.1 channels by CaBP1 and VILIP-2 has opposing effects on short-term synaptic plasticity in superior cervical ganglion neurons. Expression of CaBP1, which blocks Ca 2+ -dependent facilitation of P/Q-type Ca 2+ current, markedly reduced facilitation of synaptic transmission. VILIP-2, which blocks Ca 2+ -dependent inactivation of P/Q-type Ca 2+ current, reduced synaptic depression and increased facilitation under conditions of high release probability. These results demonstrate that activity-dependent ...

Research paper thumbnail of Direct enhancement of presynaptic calcium influx in presynaptic facilitation at Aplysia sensorimotor synapses

Molecular and Cellular Neuroscience, 2009

Regulation of synaptic transmission by modulation of the calcium influx that triggers transmitter... more Regulation of synaptic transmission by modulation of the calcium influx that triggers transmitter release underlies different forms of synaptic plasticity, and thus could contribute to learning. In the mollusk Aplysia, the neuromodulator serotonin (5-HT) increases evoked transmitter release from sensory neurons and thereby contributes to dishabituation and sensitization of defensive reflexes. We combined electrophysiological recording with fluorescence measurements of intracellular calcium in sensory neuron synapses in culture to test whether direct up-modulation by 5-HT of calcium influx triggered by single action potentials contributes to facilitation of transmitter release. We observe increases in a previously undescribed calcium influx that are strongly correlated with increases in the amplitude of the evoked postsynaptic potentials and which cannot be accounted for by action potential prolongation. Our results suggest that direct modulation of a presynaptic calcium conductance that controls neurotransmitter release contributes to the presynaptic facilitation that underlies a simple form of learning.

Research paper thumbnail of Calcium Channels and Short-term Synaptic Plasticity

Journal of Biological Chemistry, 2013

Voltage-gated Ca 2؉ channels in presynaptic nerve terminals initiate neurotransmitter release in ... more Voltage-gated Ca 2؉ channels in presynaptic nerve terminals initiate neurotransmitter release in response to depolarization by action potentials from the nerve axon. The strength of synaptic transmission is dependent on the third to fourth power of Ca 2؉ entry, placing the Ca 2؉ channels in a unique position for regulation of synaptic strength. Short-term synaptic plasticity regulates the strength of neurotransmission through facilitation and depression on the millisecond time scale and plays a key role in encoding information in the nervous system. Ca V 2.1 channels are the major source of Ca 2؉ entry for neurotransmission in the central nervous system. They are tightly regulated by Ca 2؉ , calmodulin, and related Ca 2؉ sensor proteins, which cause facilitation and inactivation of channel activity. Emerging evidence reviewed here points to this mode of regulation of Ca V 2.1 channels as a major contributor to short-term synaptic plasticity of neurotransmission and its diversity among synapses. Ca 2ϩ influx through voltage-gated Ca 2ϩ (termed Ca V) channels at presynaptic nerve terminals is an essential step in neurotransmission and plays a crucial role in short-term synaptic plasticity. The Ca V 2 subfamily is predominant in initiating synaptic transmission at fast conventional synapses (1-3). Multiple mechanisms modulate the function of presynaptic Ca V 2 channels and thereby regulate synaptic transmission (2, 4-6). Ca V 2 channels bind the ubiquitous Ca 2ϩ sensor protein calmodulin (CaM) 2 to a site in their C-terminal domain, which induces Ca 2ϩ-dependent facilitation and inactivation of Ca V 2.1 channel activity in response to repetitive stimuli (7-10). Facilitation and inactivation of Ca V 2 channel activity can cause facilitation and depression of synaptic transmission (11, 12). In this minireview, we focus on regulation of the presynaptic Ca V 2 channels by different calcium sensor proteins and the role of this mechanism in short-term synaptic plasticity.

Research paper thumbnail of Regulation of Active Zone Ca2+ Channels

Presynaptic Terminals, 2014

At the presynaptic active zone, Ca2+ influx through voltage-gated CaV2 channels triggers fast, sy... more At the presynaptic active zone, Ca2+ influx through voltage-gated CaV2 channels triggers fast, synchronous neurotransmitter release from synaptic vesicles. Synaptic vesicles localized to release sites are tightly coupled with presynaptic CaV2 channels whereby neurotransmitter release is proportional to the Ca2+ current, or the Ca2+ concentration, with the third or fourth power. CaV2 channel activity is regulated directly or indirectly by multiple mechanisms through protein-protein interactions, before and after synaptic vesicle exocytosis, resulting in fine-tuning of Ca2+ entry that effectively modulates basal neurotransmitter release and underlies presynaptic short-term plasticity. Presynaptic active zone proteins form a large complex, which tether CaV2 channels, dock and prime synaptic vesicles at release sites, and possess regulatory function. CaV2 channel modulation, which is upstream of synaptic vesicle exocytosis, that leads to changes in Ca2+ influx provides a powerful and efficient way to regulate synaptic transmission. In this chapter, we review progress toward understanding the cellular and molecular mechanisms that modulate the activity of Ca2+ channels at the presynaptic active zone. A remaining challenge is to understand how these processes work together to shape synaptic transmission and synaptic plasticity.