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Voltage-gated calcium channels couple depolarization of the cell-surface membrane to entry of calcium, which triggers secretion, contraction, neurotransmission, gene expression, and other physiological responses. They are encoded by ten genes, which generate three voltage-gated calcium channel subfamilies: CaV1; CaV2; and CaV3. At synapses, CaV2 channels form large signaling complexes in the presynaptic nerve terminal, which are responsible for the calcium entry that triggers neurotransmitter release and short-term presynaptic plasticity. CaV1 channels form signaling complexes in postsynaptic dendrites and dendritic spines, where their calcium entry induces long-term potentiation. These calcium channels are the targets of mutations and polymorphisms that alter their function and/or regulation and cause neuropsychiatric diseases, including migraine headache, cerebellar ataxia, autism, schizophrenia, bipolar disorder, and depression. This article reviews the molecular properties of calcium channels, considers their multiple roles in synaptic plasticity, and discusses their potential involvement in this wide range of neuropsychiatric diseases.

Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remains uncertain. Here we show that regulation of voltage-gated calcium (Ca2+) channel type 2.1 (CaV2.1) by neuronal Ca2+sensor (CaS) proteins controls synaptic plasticity and excitation/inhibition balance in a hippocampal circuit. Prevention of CaS protein regulation by introducing the IM-AA mutation in CaV2.1 channels in male and female mice impairs short-term synaptic facilitation at excitatory synapses of CA3 pyramidal neurons onto parvalbumin (PV)-expressing basket cells. In sharp contrast, the IM-AA mutation abolishes rapid synaptic depression in the inhibitory synapses of PV basket cells onto CA1 pyramidal neurons. These results show that CaS protein regulation of facilitation and inactivation of CaV2.1 channels controls the direction of short-term plasticity at these two synapses. Deletion of the CaS protein CaBP1/caldendrin also blocks rapid depression at PV-CA1 synapses, implicating its upregulation of inactivation of CaV2.1 channels in control of short-term synaptic plasticity at this inhibitory synapse. Studies of local-circuit function revealed reduced inhibition of CA1 pyramidal neurons by the disynaptic pathway from CA3 pyramidal cells via PV basket cells and greatly increased excitation/inhibition ratio of the direct excitatory input versus indirect inhibitory input from CA3 pyramidal neurons to CA1 pyramidal neurons. This striking defect in local-circuit function may contribute to the dramatic impairment of spatial learning and memory in IM-AA mice.SIGNIFICANCE STATEMENTMany forms of short-term synaptic plasticity in neuronal circuits rely on regulation of presynaptic voltage-gated Ca2+(CaV) channels. Regulation of CaV2.1 channels by neuronal calcium sensor (CaS) proteins controls short-term synaptic plasticity. Here we demonstrate a direct link between regulation of CaV2.1 channels and short-term synaptic plasticity in native hippocampal excitatory and inhibitory synapses. We also identify CaBP1/caldendrin as the calcium sensor interacting with CaV2.1 channels to mediate rapid synaptic depression in the inhibitory hippocampal synapses of parvalbumin-expressing basket cells to CA1 pyramidal cells. Disruption of this regulation causes altered short-term plasticity and impaired balance of hippocampal excitatory to inhibitory circuits.

Facilitation and inactivation of P/Q-type Ca2+ currents mediated by Ca2+/calmodulin binding to Ca(V)2.1 channels contribute to facilitation and rapid depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin from its binding site and differentially modulate P/Q-type Ca2 + currents, resulting in diverse patterns of short-term synaptic plasticity. Neuronal calcium sensor-1 (NCS-1, frequenin) has been shown to enhance synaptic facilitation, but the underlying mechanism is unclear. We report here that NCS-1 directly interacts with IQ-like motif and calmodulin-binding domain in the C-terminal domain of Ca(V)2.1 channel. NCS-1 reduces Ca2 +-dependent inactivation of P/Q-type Ca2+ current through interaction with the IQ-like motif and calmodulin-binding domain without affecting peak current or activation kinetics. Expression of NCS-1 in presynaptic superior cervical ganglion neurons has no effect on synaptic transmission, eliminating effects of this calcium sensor protein on endogenous N-type Ca2+ currents and the endogenous neurotransmitter release machinery. However, in superior cervical ganglion neurons expressing wild-type Ca(V)2.1 channels, co-expression of NCS-1 induces facilitation of synaptic transmission in response to paired pulses and trains of depolarizing stimuli, and this effect is lost in Ca(V)2.1 channels with mutations in the IQ-like motif and calmodulin-binding domain. These results reveal that NCS-1 directly modulates Ca(V)2.1 channels to induce short-term synaptic facilitation and further demonstrate that CaS proteins are crucial in fine-tuning short-term synaptic plasticity.

The L-type Ca2+ channel Cav1.2 controls heart rate and neuronal excitability. Qian et al . found that enhancement of Cav1.2 channel activity in the brain by β-adrenergic receptor (βAR) signaling required phosphorylation of Ser1928, whereas in the heart, this site was dispensable for βAR-mediated regulation. In contrast to those from wild-type mice, hippocampal neurons from mice, in which Ser1928 of Cav1.2 was mutated to alanine, did not exhibit increased L-type calcium channel activity in response to β-adrenergic stimulation. Phosphorylation of Ser1928 involved signaling through the β2AR, but not through the β1AR, and this phosphorylation event enabled a particular form of long-term potentiation, a process linked to learning and memory. These results were in marked contrast to βAR-mediated regulation of Cav1.2 activity in cardiomyocytes, which involved β1AR and was independent of Ser1928. This differential regulation in the heart and brain implies that tissue-specific therapeutics could be identified.

Many forms of short-term synaptic plasticity rely on regulation of presynaptic voltage-gated Ca2+ type 2.1 (CaV2.1) channels. However, the contribution of regulation of CaV2.1 channels to other forms of neuroplasticity and to learning and memory are not known. Here we have studied mice with a mutation (IM-AA) that disrupts regulation of CaV2.1 channels by calmodulin and related calcium sensor proteins. Surprisingly, we find that long-term potentiation (LTP) of synaptic transmission at the Schaffer collateral-CA1 synapse in the hippocampus is substantially weakened, even though this form of synaptic plasticity is thought to be primarily generated postsynaptically. LTP in response to θ-burst stimulation and to 100-Hz tetanic stimulation is much reduced. However, a normal level of LTP can be generated by repetitive 100-Hz stimulation or by depolarization of the postsynaptic cell to prevent block of NMDA-specific glutamate receptors by Mg2+ The ratio of postsynaptic responses of NMDA-specific glutamate receptors to those of AMPA-specific glutamate receptors is decreased, but the postsynaptic current from activation of NMDA-specific glutamate receptors is progressively increased during trains of stimuli and exceeds WT by the end of 1-s trains. Strikingly, these impairments in long-term synaptic plasticity and the previously documented impairments in short-term synaptic plasticity in IM-AA mice are associated with pronounced deficits in spatial learning and memory in context-dependent fear conditioning and in the Barnes circular maze. Thus, regulation of CaV2.1 channels by calcium sensor proteins is required for normal short-term synaptic plasticity, LTP, and spatial learning and memory in mice.

Presynaptic Ca(V)2.1 channels, which conduct P/Q-type Ca(2+) currents, initiate synaptic transmission at most synapses in the central nervous system. Regulation of Ca(V)2.1 channels by CaM contributes significantly to short term facilitation and rapid depression of synaptic transmission. Short term synaptic plasticity is diverse in form and function at different synapses, yet CaM is ubiquitously expressed. Differential regulation of Ca(V)2.1 channels by CaM-like Ca(2+) sensor (CaS) proteins differentially affects short term synaptic facilitation and rapid synaptic depression in transfected sympathetic neuron synapses. Here, we define the molecular determinants for differential regulation of Ca(V)2.1 channels by the CaS protein calcium-binding protein-1 (CaBP1) by analysis of chimeras in which the unique structural domains of CaBP1 are inserted into CaM. Our results show that the N-terminal domain, including its myristoylation site, and the second EF-hand, which is inactive in Ca(2+) binding, are the key molecular determinants of differential regulation of Ca(V)2.1 channels by CaBP1. These findings give insight into the molecular code by which CaS proteins differentially regulate Ca(V)2.1 channel function and provide diversity of form and function of short term synaptic plasticity.

SUMMARY Activation of CaV2.1 voltage-gated calcium channels is facilitated by preceding calcium entry. Such self-modulatory facilitation is thought to contribute to synaptic facilitation. Using knockin mice with mutated CaV2.1 channels that do not facilitate (Ca IM-AA mice), we surprisingly found that, under conditions of physiological calcium and near-physiological temperatures, synaptic facilitation at hippocampal CA3 to CA1 synapses was not attenuated in Ca IM-AA mice and facilitation was paradoxically more prominent at two cerebellar synapses. Enhanced facilitation at these synapses is consistent with a decrease in initial calcium entry, suggested by an action-potential-evoked CaV2.1 current reduction in Purkinje cells from Ca IM-AA mice. In wild-type mice, CaV2.1 facilitation during high-frequency action potential trains was very small. Thus, for the synapses studied, facilitation of calcium entry through CaV2.1 channels makes surprisingly little contribution to synaptic facilitation under physiological conditions. Instead, CaV2.1 facilitation offsets CaV2.1 inactivation to produce remarkably stable calcium influx during high-frequency activation., Graphical Abstract, In Brief Weyrer et al. use Ca IM-AA mice in which CaV2.1 calcium channel facilitation is eliminated to study synaptic facilitation at hippocampal and cerebellar synapses. Under conditions of physiological temperature, external calcium, and presynaptic waveforms, facilitation of CaV2.1 channels is small and does not contribute to synaptic facilitation at these synapses.

Na+-activated K+ (KNa) channels can be activated by Na+ influx via ionotropic receptors and play a role in shaping synaptic transmission. In expression systems, KNa channels are modulated by G protein–coupled receptors, but such a modulation has not been shown for the native channels. In this study, we examined whether KNa channels coupled to AMPA receptors are modulated by metabotropic glutamate receptors (mGluRs) in lamprey spinal cord neurons. Activation of mGluR1 strongly inhibited the AMPA-induced KNa current. However, when intracellular Ca2+ was chelated with 1,2-bis(2-aminophenoxy)ethane- N,N,N′, N′-tetraacetic acid (BAPTA), the KNa current was enhanced by mGluR1. Activation of protein kinase C (PKC) mimicked the inhibitory effect of mGluR1 on the KNa current. Blockade of PKC prevented the mGluR1-induced inhibition of the KNa current, but did not affect the enhancement of the current seen in BAPTA. Together these results suggest that mGluR1 can differentially modulate AMPA-induced KNa current in a Ca2+- and PKC-dependent manner.

Metabotropic glutamate receptor subtype 1 (mGluR1) contributes importantly to the activity of the spinal locomotor network. For example, it potentiates NMDA current and inhibits leak conductance in lamprey spinal cord neurons. In this study we examined the signalling pathways underlying the mGluR1 modulation of NMDA receptors and leak channels, respectively. Our results show that mGluR1-induced potentiation of NMDA current required activation of phospholipase C (PLC) and was independent of the increase in the intracellular Ca2+ concentration because it was unaffected by the Ca2+ chelator BAPTA and by depletion of the internal Ca2+ stores with thapsigargin. We also show that the mGluR1-mediated inhibition of leak channels is mediated by activation of G-proteins. Finally, we show that blockade of protein kinase C (PKC) abolished the mGluR1-induced inhibition of leak current without affecting the potentiation of NMDA receptors. The contribution of mGluR1-mediated modulation of leak channels to the potentiation of the locomotor cycle frequency was assessed during fictive locomotion. Blockade of PKC significantly decreased the short-term potentiation of locomotor cycle frequency by mGluR1. These results show that the effects of mGluR1 activation on the two cellular targets, the NMDA receptor and leak channels, are mediated through separate signalling pathways.

Na + -activated K + (K Na ) channels are expressed in neurons and are activated by Na + influx through voltage-dependent channels or ionotropic receptors, yet their function remains unclear. Here we show that K Na channels are associated with AMPA receptors and that their activation depresses synaptic responses. Synaptic activation of K Na channels by Na + transients via AMPA receptors shapes the decay of AMPA-mediated current as well as the amplitude of the synaptic potential. Thus, the coupling between K Na channels and AMPA receptors by synaptically induced Na + transients represents an inherent negative feedback mechanism that scales down the magnitude of excitatory synaptic responses.

Stem cell self-renewal implies proliferation under continued maintenance of multipotency. Small changes in numbers of stem cells may lead to large differences in differentiated cell numbers, resulting in significant physiological consequences. Proliferation is typically regulated in the G1 phase, which is associated with differentiation and cell cycle arrest. However, embryonic stem (ES) cells may lack a G1 checkpoint. Regulation of proliferation in the 'DNA damage' S/G2 cell cycle checkpoint pathway is known for its role in the maintenance of chromatin structural integrity. Here we show that autocrine/paracrine gamma-aminobutyric acid (GABA) signalling by means of GABA(A) receptors negatively controls ES cell and peripheral neural crest stem (NCS) cell proliferation, preimplantation embryonic growth and proliferation in the boundary-cap stem cell niche, resulting in an attenuation of neuronal progenies from this stem cell niche. Activation of GABA(A) receptors leads to hyperpolarization, increased cell volume and accumulation of stem cells in S phase, thereby causing a rapid decrease in cell proliferation. GABA(A) receptors signal through S-phase checkpoint kinases of the phosphatidylinositol-3-OH kinase-related kinase family and the histone variant H2AX. This signalling pathway critically regulates proliferation independently of differentiation, apoptosis and overt damage to DNA. These results indicate the presence of a fundamentally different mechanism of proliferation control in these stem cells, in comparison with most somatic cells, involving proteins in the DNA damage checkpoint pathway.

Short-term synaptic plasticity is induced by calcium (Ca(2+)) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated CaV2.1 Ca(2+) channels by Ca(2+) sensor proteins induces facilitation of Ca(2+) currents and synaptic facilitation in cultured neurons expressing exogenous CaV2.1 channels. However, it is unknown whether this mechanism contributes to facilitation in native synapses. We introduced the IM-AA mutation into the IQ-like motif (IM) of the Ca(2+) sensor binding site. This mutation does not alter voltage dependence or kinetics of CaV2.1 currents, or frequency or amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs); however, synaptic facilitation is completely blocked in excitatory glutamatergic synapses in hippocampal autaptic cultures. In acutely prepared hippocampal slices, frequency and amplitude of mEPSCs and amplitudes of evoked EPSCs are unaltered. In contrast, short-term synaptic facilitation in response to paired stimuli is reduced by ∼ 50%. In the presence of EGTA-AM to prevent global increases in free Ca(2+), the IM-AA mutation completely blocks short-term synaptic facilitation, indicating that synaptic facilitation by brief, local increases in Ca(2+) is dependent upon regulation of CaV2.1 channels by Ca(2+) sensor proteins. In response to trains of action potentials, synaptic facilitation is reduced in IM-AA synapses in initial stimuli, consistent with results of paired-pulse experiments; however, synaptic depression is also delayed, resulting in sustained increases in amplitudes of later EPSCs during trains of 10 stimuli at 10-20 Hz. Evidently, regulation of CaV2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses.

Facilitation and inactivation of P/Q-type calcium (Ca(2+)) currents through the regulation of voltage-gated Ca(2+) (CaV) 2.1 channels by Ca(2+) sensor (CaS) proteins contributes to the facilitation and rapid depression of synaptic transmission in cultured neurons that transiently express CaV2.1 channels. To examine the modulation of endogenous CaV2.1 channels by CaS proteins in native synapses, we introduced a mutation (IM-AA) into the CaS protein-binding site in the C-terminal domain of CaV2.1 channels in mice, and tested synaptic facilitation and depression in neuromuscular junction synapses that use exclusively CaV2.1 channels for Ca(2+) entry that triggers synaptic transmission. Even though basal synaptic transmission was unaltered in the neuromuscular synapses in IM-AA mice, we found reduced short-term facilitation in response to paired stimuli at short interstimulus intervals in IM-AA synapses. In response to trains of action potentials, we found increased facilitation at lower frequencies (10-30 Hz) in IM-AA synapses accompanied by slowed synaptic depression, whereas synaptic facilitation was reduced at high stimulus frequencies (50-100 Hz) that would induce strong muscle contraction. As a consequence of altered regulation of CaV2.1 channels, the hindlimb tibialis anterior muscle in IM-AA mice exhibited reduced peak force in response to 50 Hz stimulation and increased muscle fatigue. The IM-AA mice also had impaired motor control, exercise capacity, and grip strength. Taken together, our results indicate that regulation of CaV2.1 channels by CaS proteins is essential for normal synaptic plasticity at the neuromuscular junction and for muscle strength, endurance, and motor coordination in mice in vivo.

Potassium channels play an important role in controlling neuronal firing and synaptic interactions. Na+-activated K+ ( KNa) channels have been shown to exist in neurons in different regions of the CNS, but their physiological function has been difficult to assess. In this study, we have examined if neurons in the spinal cord possess KNa currents. We used whole cell recordings from isolated spinal cord neurons in lamprey. These neurons display two different KNa currents. The first was transient and activated by the Na+ influx during the action potentials, and it was abolished when Na+ channels were blocked by tetrodotoxin. The second KNa current was sustained and persisted in tetrodotoxin. Both KNa currents were abolished when Na+ was substituted with choline or N-methyl-d-glucamine, indicating that they are indeed dependent on Na+ influx into neurons. When Na+ was substituted with Li+, the amplitude of the inward current was unchanged, whereas the transient KNa current was reduced but not abolished. This suggests that the transient KNa current is partially activated by Li+. These two KNa currents have different roles in controlling the action potential waveform. The transient KNa appears to act as a negative feedback mechanism sensing the Na+ influx underlying the action potential and may thus be critical for setting the amplitude and duration of the action potential. The sustained KNa current has a slow kinetic of activation and may underlie the slow Ca2+-independent afterhyperpolarization mediated by repetitive firing in lamprey spinal cord neurons.

Na+-activated K+ channels (K(Na)) exist in different types of neurones and their activation has been shown to depend on Na+ influx via voltage-activated channels. However, one major route for Na+ influx into neurones is through ionotropic receptors and its role in activating K(Na) is still unclear. We have examined whether Na+ influx induced by activation of AMPA receptors can activate K(Na) in lamprey spinal cord neurones. Our results showed that the application of AMPA induced not only the characteristic inward current but also produced an outward current outlasting the activation of the receptors. This outward current was mediated by K+ and was abolished when Na+ was substituted with Li+. The AMPA-mediated K(Na) current was completely blocked by quinidine but was not modulated by increased intracellular Cl- concentration or ATP. Thus, Na+ influx via AMPA receptor channels activates K(Na) with properties similar to Slack channels. The AMPA-activated K(Na) may act as an inherent negative feedback mechanism to regulate the homeostasis of excitation.

The generation of activity in the central nervous system requires precise tuning of cellular properties and synaptic transmission. Neural networks in the spinal cord produce coordinated locomotor movements. Synapses in these networks need to be equipped with multiple mechanisms that regulate their operation over varying regimes to produce locomotor activity at different frequencies. Using the in vitro lamprey spinal cord, we explored whether Ca2+ influx via different routes in postsynaptic soma and dendrites and in presynaptic terminals can activate apamin-sensitive Ca2+-activated K+ (SK) channels and thereby shape synaptic transmission. We show that postsynaptic SK channels are tightly coupled to Ca2+ influx via NMDA receptors. Activation of these channels by synaptically induced NMDA-dependent Ca2+ transients restrains the time course of the synaptic current and the amplitude of the synaptic potential. In addition, presynaptic SK channels are activated by Ca2+ influx via voltage-gated channels and control the waveform of the action potential and the resulting Ca2+ dynamics in the axon terminals. The coupling of SK channels to different Ca2+ sources, pre- and postsynaptically, acts as a negative feedback mechanism to shape synaptic transmission. Thus SK channels can play a pivotal role in setting the dynamic range of synapses and enabling short-term plasticity in the spinal locomotor network.

Coherent network activity among assemblies of interconnected cells is essential for diverse functions in the adult brain. However, cellular networks before formations of chemical synapses are poorly understood. Here, embryonic stem cell-derived neural progenitors were found to form networks exhibiting synchronous calcium ion (Ca(2+)) activity that stimulated cell proliferation. Immature neural cells established circuits that propagated electrical signals between neighboring cells, thereby activating voltage-gated Ca(2+) channels that triggered Ca(2+) oscillations. These network circuits were dependent on gap junctions, because blocking prevented electrotonic transmission both in vitro and in vivo. Inhibiting connexin 43 gap junctions abolished network activity, suppressed proliferation, and affected embryonic cortical layer formation. Cross-correlation analysis revealed highly correlated Ca(2+) activities in small-world networks that followed a scale-free topology. Graph theory predicts that such network designs are effective for biological systems. Taken together, these results demonstrate that immature cells in the developing brain organize in small-world networks that critically regulate neural progenitor proliferation.

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.

We have identified an asynchronously activated Ca 2+ current through voltage-gated Ca 2+ (Ca V )-2.1 and Ca V 2.2 channels, which conduct P/Q- and N-type Ca 2+ currents that initiate neurotransmitter release. In nonneuronal cells expressing Ca V 2.1 or Ca V 2.2 channels and in hippocampal neurons, prolonged Ca 2+ entry activates a Ca 2+ current, I Async , which is observed on repolarization and decays slowly with a half-time of 150–300 ms. I Async is not observed after L-type Ca 2+ currents of similar size conducted by Ca V 1.2 channels. I Async is Ca 2+ -selective, and it is unaffected by changes in Na + , K + , Cl − , or H + or by inhibitors of a broad range of ion channels. During trains of repetitive depolarizations, I Async increases in a pulse-wise manner, providing Ca 2+ entry that persists between depolarizations. In single-cultured hippocampal neurons, trains of depolarizations evoke excitatory postsynaptic currents that show facilitation followed by depression accompanied by asynchronous postsynaptic currents that increase steadily during the train in parallel with I Async . I Async is much larger for slowly inactivating Ca V 2.1 channels containing β 2a -subunits than for rapidly inactivating channels containing β 1b -subunits. I Async requires global rises in intracellular Ca 2+ , because it is blocked when Ca 2+ is chelated by 10 mM EGTA in the patch pipette. Neither mutations that prevent Ca 2+ binding to calmodulin nor mutations that prevent calmodulin regulation of Ca V 2.1 block I Async . The rise of I Async during trains of stimuli, its decay after repolarization, its dependence on global increases of Ca 2+ , and its enhancement by β 2a -subunits all resemble asynchronous release, suggesting that I Async is a Ca 2+ source for asynchronous neurotransmission.

CaV2.1 channels, which conduct P/Q-type Ca2+ currents, initiate synaptic transmission at most synapses in the central nervous system. Ca2+/calmodulin-dependent facilitation and inactivation of these channels contributes to short-term facilitation and depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin (CaM) from its binding site, differentially regulate CaV2.1 channels, and contribute to the diversity of short-term synaptic plasticity. The neuronal calcium sensor protein visinin-like protein 2 (VILIP-2) inhibits inactivation and enhances facilitation of CaV2.1 channels. Here we examine the molecular determinants for differential regulation of CaV2.1 channels by VILIP-2 and CaM by construction and functional analysis of chimeras in which the functional domains of VILIP-2 are substituted in CaM. Our results show that the N-terminal domain, including its myristoylation site, the central α-helix, and the C-terminal lobe containing EF-hands 3 and 4 of VILIP-2 are sufficient to transfer its regulatory properties to CaM. This regulation by VILIP-2 requires binding to the IQ-like domain of CaV2.1 channels. Our results identify the essential molecular determinants of differential regulation of CaV2.1 channels by VILIP-2 and define the molecular code that these proteins use to control short-term synaptic plasticity.

Discrete neural networks in the central nervous system generate the repertoire of motor behavior necessary for animal survival. The final motor output of these networks is the result of the anatomical connectivity between the individual neurons and also their biophysical properties as well as the dynamics of their synaptic transmission. To illustrate how this processing takes place to produce coordinated motor activity, we have summarized some of the results available from the lamprey spinal locomotor network. The detailed knowledge available in this model system on the organization of the network together with the properties of the constituent neurons and the modulatory systems allows us to determine how the impact of specific ion channels and receptors is translated to the global activity of the locomotor circuitry. Understanding the logic of the neuronal and synaptic processing within the locomotor network will provide information about not only their normal operation but also how they react to disruption such as injuries or trauma.

Discrete neural networks in the central nervous system generate the repertoire of motor behavior necessary for animal survival. The final motor output of these networks is the result of the anatomical connectivity between the individual neurons and also their biophysical properties as well as the dynamics of their synaptic transmission. To illustrate how this processing takes place to produce coordinated motor activity, we have summarized some of the results available from the lamprey spinal locomotor network. The detailed knowledge available in this model system on the organization of the network together with the properties of the constituent neurons and the modulatory systems allows us to determine how the impact of specific ion channels and receptors is translated to the global activity of the locomotor circuitry. Understanding the logic of the neuronal and synaptic processing within the locomotor network will provide information about not only their normal operation but also how they react to disruption such as injuries or trauma.

Metabotropic glutamate receptor subtype 1 (mGluR1) contributes importantly to the activity of the spinal locomotor network. For example, it potentiates NMDA current and inhibits leak conductance in lamprey spinal cord neurons. In this study we examined the signalling pathways underlying the mGluR1 modulation of NMDA receptors and leak channels, respectively. Our results show that mGluR1-induced potentiation of NMDA current required activation of phospholipase C (PLC) and was independent of the increase in the intracellular Ca2+ concentration because it was unaffected by the Ca2+ chelator BAPTA and by depletion of the internal Ca2+ stores with thapsigargin. We also show that the mGluR1-mediated inhibition of leak channels is mediated by activation of G-proteins. Finally, we show that blockade of protein kinase C (PKC) abolished the mGluR1-induced inhibition of leak current without affecting the potentiation of NMDA receptors. The contribution of mGluR1-mediated modulation of leak channels to the potentiation of the locomotor cycle frequency was assessed during fictive locomotion. Blockade of PKC significantly decreased the short-term potentiation of locomotor cycle frequency by mGluR1. These results show that the effects of mGluR1 activation on the two cellular targets, the NMDA receptor and leak channels, are mediated through separate signalling pathways.

Dendritic growth is pivotal in the neurogenesis of cortical neurons. The sodium pump, or Na,K-ATPase, is an evolutionarily conserved protein that, in addition to its central role in establishing the electrochemical gradient, has recently been reported to function as a receptor and signaling mediator. Although a large body of evidence points toward a dual function for the Na,K-ATPase, few biological implications of this signaling pathway have been described. Here we report that Na,K-ATPase signal transduction triggers dendritic growth as well as a transcriptional program dependent on cAMP response element binding protein (CREB) and cAMP response element (CRE)-mediated gene expression, primarily regulated via Ca 2+ /calmodulin-dependent protein (CaM) kinases. The signaling cascade mediating dendritic arbor growth also involves intracellular Ca 2+ oscillations and sustained phosphorylation of mitogen-activated protein (MAP) kinases. Thus, our results suggest a novel role for the Na,K-ATPase as a modulator of dendritic growth in developing neurons.