Ion Channels And Neuronal Activity Research Paper

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The most fundamental mechanism for imparting information in the nervous system is the opening of ion channels. This responsibility begins early in life, where opening of ion channels in progenitor cells induces neuronal differentiation. Indeed, ion channels mold the growth and behavior of neurons throughout each phase of the life span. While there are many different classes of ion channel s involved in regulating nervous system activity, Ca2+ entry serves as the internal ionic message of neural experience. Developmentally, calcium triggers differentiation, guides the growth of neuronal processes, and contributes to the selective elimination of neurons. Ca2+ mediates neurotransmitter release, the simplest form of interneuron communication, and its entry is the primary intracellular event for encoding the frequency and number action potentials generated pre- and postsynaptically. Activity- or use-dependent increases in Ca2+ serve as an intracellular message for initiating neuronal plasticity which may be involved in circuit modifications required for learning a memory. Finally, completing the cycle of neuronal ontogeny, Ca2+ in excess triggers a cascade of mechanisms leading to neuronal degeneration during senescence and age-related disease.

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1. Activity-Dependent Increases In Neuronal Ca2+

Internal Ca2+ is maintained at extremely low concentrations creating an enormous driving force for its movement into the cytoplasm from internal stores or the extracellular space. Ca2+ levels are estimated to be at about 100 nM in neurons at their re sting hyperpolarized state, while extracellular Ca2+ is in the 2–3 mM range and 10 µM to 1 mM inside the endoplasmic reticulum (Ghosh and Greenberg 1996 , Mattson et al. 2000). The gating mechanisms for Ca2+ entry into the cell’s cytoplasm includes plasma membrane voltage-dependent Ca2+ channels (VDCC), plasma membrane neurotransmitter or ligand-activated channels, and Ca2+ release from internal stores. All of these mechanisms a re recruited by neuronal activity, they experience Ca2+ mediated feedback regulation, and they are modulated by neurotransmitter activation of G-proteins (Lee et al. 1999, Zhang et al. 1998, Zamponi and Snu tch 1998, Zuhlke et al. 1999). Each mechanism of Ca2+ entry is compartmentalized to produce localized increases in intracellular Ca2+ and site-specific activation of Ca2+ sensitive pathways (Magee et al. 1998, Neher 199 8, Yuste et al. 2000).

Adaptive thresholds for Ca2+ entry ensure its action as a second messenger will reflect high levels of neuronal activity. Voltage-gated and neurotransmitter gated channels interact during periods of neuronal activity to determine the degree of Ca2+ entry and thus the direction of Ca2+ -mediated adaptation. The classic sequence for initiating Ca2+ entry begins with presynaptic release of neurotransmitter acting postsynaptically to depolarize the cell beyond the threshold for triggering an action potential (Colquhoun and Sakmann 1998). The pioneering work of Hodgkin, Huxley, and Katz demonstrated action potentials were initiated by activating voltage-dependent Na+ channels and rapidly terminated by the combined action of Na+ channel inactivation and the opposing activation of voltage-dependent K channels (Hodgkin et al. 1952). Activation of VDCCs is facilitated by the rapid depolarization initiated by Na+ channel activation, but it is not an +absolute requirement. High- and low-threshold Ca2+ -mediated action potentials can be triggered by depolarization independent of Na+ channel activation (Magee et al. 1998, Huguenard 1996). The duration and peak depolarization of t he action potential, and consequently the extent of Ca2+ entry, is limited by activation of voltage-dependent K+ channels and intrinsic kinetics of Ca2+ channel inactivation.

Unique patterns of Ca2+ can be achieved by the selective expression of ion channels in different populations of nerve cells. For example, the expression of inwardly rectifying K+ (Kir) channels raises the threshold for action potential generation by hyperpolarizing the resting membrane potential of striatal neurons, while the expression and interaction of low-threshold Ca2+ channels (T-type), Ca2+ -activated K+ channels (slo), and hyperpolarization activated K+ channels (IH) contribute to regular, intrinsic firing in neurons of the substantianigra and thalamus (Huguenard 1996, Santoro et al. 2000, Wilson and Callaway 2000). Regional differences in ion channel distribution can also create microenvironments of Ca2+ control within the cell. Clustering of Na+, K+, and Ca2+ channels in dendrites create local sites for integrating synaptic input (Magee et al. 1998, Safronov 1 999), and direct association of P/Q and N-type Ca2+ channels with vesicle fusion proteins mediates activity-dependent release of neurotransmitter in synaptic terminals (Goda and Sudhof 1997, Neher 1998).

The molecular diversity of ion channels present in neurons creates opportunity for exquisite control of Ca2+ influx through differences in gating mechanisms and kinetics of activation and inactivation (Catterall 1995, Ghosh and Greenberg 1995). Calcium channels are heteroligomeric complexes containing α1, α2δ and β subunits. Ca+ channels contain a single α subunit which serves as a pore and voltage sensor. Nine α subunit genes have been identified, corresponding to each type of VDCC channel previously categorized by pharmacology. α1A encodes for ω-Aga IVA sensitive P-type, α1B encodes for ω-Ctx GVIA sensitive N-type, α1C, α1D and α1S all encode for dihydropyridine sensitive L-type and α1G and α1H encode for Ni2+-sensitive T-type + calcium channels (Zamponi and Snutch 1998). K+ channels represent a much larger and more diverse collection of ion channels. At present, nine families of voltage-activated K+ channels are described (Kaczorowski and Garcia 1999). Many are derived from homologues of Drosophila channel genes Shaker, Shah, Shaw, and Shal, referred to as KV1, KV2, KV3, and KV4 in mammals. They usually form homotetrameric channels, but association with β- subunits can alter channel kinetics (Kaczorowski and Garcia 1999). A separate class of K+ channel fundamental in regulating neuronal excitability is Ca2+ – activated K+ channels. They are classified by single channel conductances of 2–25 pS (small or SK channel), 25–100 pS (intermediate or IK channel), and 100–300 pS (large or BK channel) (Kaczorowski and Garcia 1999). Ca2+-activated K+ channels serve as an activity-dependent feedback mechanism for reducing neuron firing frequency and returning the membrane potential back to its resting state.

Excitatory synaptic input increases intracellular Ca2+ directly, by activating ionotropic and metabotropic glutamate receptors, and secondarily by driving the membrane potential beyond the voltage-dependent threshold for activating VDCCs. The cooperation of these mechanisms ensures robust Ca2+ signals in response to strong synaptic drive. Ionotropic glutamate receptors (AMPA, kainate, and NMDA receptors) are the postsynaptic mediators of fast excitatory synaptic transmission. Functional ionotropic glutamate receptors contain four or five structurally related subunits. The combination of subunits GluR1–4 make functional AMPA receptors, GluR5–7 and KA1–2 make kainate receptors, and NR1 and NR2A-D make NMDA receptors (Bigge 1999). Flip or flop splice variants of AMPA receptor subunits influence gating kinetics. AMPA receptors generally have low Ca2+ permeability, due to the Q*R site of GluR2 subunits. GluR2 is the most common subunit found in the brain, but examples of receptors without GluR2 exist and are implicated in Ca2+-dependent changes in neuronal physiology (Conti and Weinberg 1999, Bigge 1999). NMDA receptors have greater glutamate affinity than AMPA receptors, slower activation and deactivation kinetics, and they are highly permeable to Ca2+. The Ca2+ conductance/Na+ conductance is > 5 for NMDA receptors, 2 for AMPA receptors lacking GluR2, and 0.1 for AMPA receptors containing GluR2 (Conti and Weinberg 1999). The combined action of greater Ca2+ permeability and slower channel inactivation results in dramatically more Ca2+ influx for NMDA receptors. NMDA receptors are made of NR1 and NR2 heterodimer complexes and generally composed of 4–5 subunits. NR1 is essential for channel function and NR2 confers the voltage-dependent Mg2+ block and glycine modulation of NMDA receptors (Conti and Weinberg 1999). The voltage-dependent Mg2+ -block acts as an activity sensor, allowing large increases in intracellular Ca2+ only when the depolarization threshold for releasing the Mg2+ block is exceeded. Kainate receptors, like AMPA receptors, lack voltage dependency. Compared to AMPA receptors, kainate receptors contribute little to the peak postsynaptic response, but their slower decay kinetics results in comparable charge transfer (Ferking and Nicoll 2000). Kainate receptors also mediate presynaptic inhibition of excitatory and inhibitory synapses in the hippocampus.

Slow excitatory synaptic events mediated by activation of metabotropic glutamate receptors (mGluRs) is another important mechanism for elevating intracellular Ca+2. Group-I mGluRs stimulate phospholipase C via GTP-binding proteins. Phospholipase C cleaves phosphoinositol-(4,5)-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5 triphosphate (IP3). DAG activates protein kinase C (PKC) and I(1,4,5)P3 activates IP3 receptors located on the surface of the smooth endoplasmic reticulum (Fagni et al. 2000, Mattson et al. 2000). IP3 receptors trigger the release of Ca2+ stored in the endoplasmic reticulum at concentrations of 10–100 µM (Mattson et al. 2000). Other neurotransmitters use the same mechanism for releasing Ca2+ from intracellular stores, but glutamate is by far the most ubiquitous.

2. Activity-Dependent Control Of Neuronal Development

Ca2+ influx stimulates differentiation and directs the course of development in excitable cells (Spitzer et al. 1994). VDCCs, ionotropic glutamate receptors, an d mGluRs all participate in regulating intracellular Ca2+ at key steps in neuronal development. Glutamate activation of NMDA and AMPA receptors induces proliferation of progenitor cells during neurogenesis and their migration to appropriate cell layers (Haydar et al. 2000). Evidence also exists for neurogenesis mediated by Ca2+ entry through voltage-dependent L- type Ca2+ channels and Ca2+ waves mediated by release of Ca2+ from intracellular stores. In postmitotic cells, Ca2+ continues to direct neuronal differentiation by influencing ion channel expression, neurotransmitter phenotype, growth factor express ion, and neurite extension (Spitzer et al. 1994). Ca2+ influx through VDCCs (Land N-type) stimulate cell adhesion molecules (CAMs) (NCAM, cadherin, and L1) to promote neurite outgrowth via CAM-mediated cell to cell interactions and the binding of CAM to actin based cytoskeleton (Doherty and Walsh 1994). Ca2+ may initiate neurite extension by binding to calmodulin (CaM) and phosphorylating microtubule associate proteins (MAP2) through the activation of Ca2+/ CaM-dependent protein kinase II and IV (Kuhn et al. 1998). A parallel mechanism implicated in MAP phosphorylation is the mitogen activated protein kinase (MAPKs) pathway stimulated by mGluR activation (Quinlin and Halpain 1996). It is clear that Ca2+ -mediated remodeling is based upon a Ca2+ set point, since differences in responses exist depending on the Ca2+ level achieved and the neuronal population examined. Some neurons experience growth cone collapse with increase s in Ca2+ , due to severing of microfilaments by Ca2+-activated gelsolin (Neely and Nichols 1995). Support for this mechanism comes from the observation of downregulated VDCCs coincident with neurite extension and increases in neuronal activity producing decreases in CAM expression.

Protein synthesis is also critical to activity-dependent plasticity and growth, a process Ca2+ mediates through interacting steps of protein phosphorylation (Ghosh and Greenberg 1995). Activity-dependent increases in Ca2+ stimulate the expression of immediate early genes like c-fos and c-jun, as well as delayed ‘effector’ genes for neurotrophins and, in a mechanism of positive feedback, genes for VDCCs, NMDA receptors, and AMPA receptors (Ghosh and Greenberg 1995). The pattern of gene expression is dependent on the pattern of neuronal activity and Ca2+ accumulation. Intracellular pathways appear to act in parallel to alter gene expression, but they may respond differentially to changes in Ca2+ concentration. A final point of convergence for Ca2+ stimulated pathways is phosphorylation of cAMP responsive element binding protein (CREB), which activates RNA polymerase by forming a complex with CREB-binding protein (CRP). The independent path – ways proposed to trigger this mechanism include Ca2+ activation of Ras/mitogen activated protein kinase (MAPK) pathway, Ca2+ activation of adenlyate cyclase and subsequently protein kinase A (PKA) and Ca2+ binding to CaM, and activation of Ca2+ /CaM kinase II and IV (Ghosh and Greenberg 1995).

Aclear division does not exist between the actions of Ca2+ and neurotrophins in driving activity-dependent change in neurons. Activity not only increases intracellular Ca2+, but it also causes the release of neurotrophins, and neurotrophins and Ca2+ produce similar responses in nerve cells (McAllister et al. 1999). Ca2+ and neurotrophins both trigger the Ras-MAPK pathway to change gene expression, neurotrophins by binding to membra ne-bound tyrosine kinase (trk) receptors, and Ca2+ by activating Ras directly (Heumann 1994). Neurotrophins have both directrapid and slow modulatory effects on ion channels involved in excitation (Benedikt and Poo 1996). Neurotrophins cause rapid depolarizations by activating Na+ channels linked to trk receptors and they modulate glutamate-activated channels and intrinsic voltage-activated channels to increase intracellular Ca2+ (Jarvis et al. 1997, Kaflitz et al. 1999). Neurotrophins also increase neuronal excitability and thus Ca2+ influx through acute inhibition of Kir3.1, Kir3.4, and Kir2.1 (Wischmeyer et al. 1998). Neurotrophins also act presynaptically to increase neurotransmitter release (McAllister et al. 1999). Testament to the intimate relationship between neurotrophins and Ca2+, neurotrophins produce long-term changes in Ca2+ entry by increasing the expression of VDCCs, NMDA receptors, and AMP A receptors, and activity-dependent increases in Ca2+ produce a reciprocal increase in neurotrophin expression (McAllister et al. 1999).

The gearing of neurons toward excitation during development is clearly illustrated by the unique behavior displayed by neurotransmitter activated channels early in development. Embryonic synaptic AMPA receptors are highly Ca2+ permeable and mEPSC (minature excitatory postsynaptic current) amplitude can be more than twofold larger than at mature synapses (Rohrbough and Spitzer 1999). Postnatal neurons preferentially express flip variants of AMPA receptors, which increase the depolarization-mediated Ca2+ signal by slowing desensitization (Conti and Wienberg 1999). It should be noted, however, that many synapses show only functional NMDA receptors and only with activity to ‘silent’ AMPA receptors appear (Petralia et al. 1999). Early postnatal development also shows a shift in the molecular structure and physiological properties of NMDA receptors. NR2B subunits are preferentially expressed early in development and they show less voltage-dependent block by Mg2+ and slower kinetics, properties which lower the threshold for Ca2+ entry during synaptic excitation. With maturity, there is a shift to NR2A and NR2C subunits which increase the Mg2+ block and speed up the NMDA activated response. This postnatal disposition toward synaptic excitation is augmented by a developmental shift in the property of GABAA receptor mediated inhibition (Ben-Ari et al. 1997). Rather than inhibiting action potential generation and VDCC activation, as is seen in adults, immature GABAA synapses cause slow depolarizations triggering bursts of action potentials and Ca2+ influx through VDCCs (Ben-Ari et al. 1997). Later in development, the Cl gradient changes resulting in hyperpolarizing GABAA responses and an inhibition of action potential generation and Ca2+ activation (Ben-Ari et al. 1997).

3. Activity And Synaptic Function

Ca2+ entering presynaptic terminals during action potentials stimulates the fusion of synaptic vesicles with the presynaptic membrane and the release of neurotransmitter into the synaptic cleft. P/Q and N- type Ca2+ channels are the primary VDCCs subserving this function in the central nervo us system (Goda and Sudhof 1997). Entrance of Ca2+ through individual channels is proposed to form microdomains, where Ca2+ levels may reach as high as 100 µM (Neher 1998). It is proposed that ‘core complex’ proteins of the synaptic fusion machinery maximize their proximity to these domains by binding syntaxin to Ca2+ channels (Go da and Sudhof 1997). Prior to and independent of Ca2+ influx, synaptic vesicles dock to the presynaptic membrane in active zones and undergo priming to make them ready for releasing neurotransmitter with Ca2+ Ca2+ influx (Goda and Sudhof 1997). The docking and priming steps are mediated by an interaction of a ‘core complex’ of NSF attachment protein receptors (SNAREs) located on the vesicle (v-SNARE) and attachment SNAREs located on the target membrane (t-SNARE). The core complex or SNARE is made up of syntaxin and synaptosome-associated membrane protein of 25 kDa (SNAP-25), which are localized in the synaptic plasma membrane, and the vesicular protein synaptobrevin (also known as vesicle associated membrane protein; VAMP) (Goda and Sudhof 1997). The process of vesicle fusion and neurotransmitter release is believed to be mediated by the interaction of the synaptotagmin Ca2+ sensor with the ‘core complex.’ Synaptotagmin I and II are the leading candidates as Ca2+ sensors, although other presynaptic proteins with Ca2+ C2 -binding domains are proposed to serve the same function (Goda and Sudhof 1997). The mechanism for fusion is proposed to be a rapid electrostatic or conformational change in the fusion complex mediated by Ca2+ binding to synaptotagmin (Goda and Sudhof 1997). The vesicle collapses into the membrane and is retrieved away from the active zone by a clathrin-dependent mechanism involving the GTPase dynamin I (Cremona and De Camilli 1997).

Invasion of the presynaptic terminal by multiple action potentials results in a short-term change in the probability of vesicle fusion and the release of neurotransmitter. Depending on the number and timing of the action potentials, and thus the degree and duration of Ca2+ increase, the processes of facilitation (time constant less than one second), augmentation (time constant of several seconds), and potentiation (time constant of a few minutes) are initiated (Zucker 1999). One mechanism proposed for mediating short-term synaptic enhancement is the binding of Ca2+ to synapsin I. Synapsin I is a Ca2+ -regulated ATPase which binds to actin and may facilitate vesicle transport via the actin matrix (Zucker 1999). Other mechanisms proposed to participate in short-term synaptic plasticity include facilitating actions of synaptotagmin and Ca2+ -dependent facilitation of presynaptic Ca2+ currents (Zucker 1999). An exciting new explanation for the longest form of short-term plasticity, PTP, is based on Ca2+ dumping by mitochondria following mitochondrial sequestration of Ca2+ during spike trains (Zucker 1999). New studies indicate another key role for Ca2+ in mediating short-term synaptic plasticity lies in a clathrin-independent form of rapid endocytosis of synaptic vesicles. The proposed mechanism suggests that Ca2+ bin ds to synaptophysin during repeated excitation and Ca2+ -stimulated synaptophysin binds to dynamin I to produce rapid endocytosis (Daley et al. 2000).

Large and sustained increases in intracellular Ca2+ on the postsynaptic side of the synapse is the primary event for inducing long-term forms of synaptic plasticity or long-term depression (LTD) and long-term potentiation (LTP). Critical to determining whether LT P or LTD occurs are the extent and kinetics of the Ca2+ signal and the molecular mechanism underlying the Ca2+ increase (Zucker 1999). These factors and other mechanisms vary considerably between brain areas. Based on cortical and cerebellar studies, a few general themes emerge. Ca2+ entry through NMDA receptors is a critical event in the induction of LTP and the Mg2+ block of these receptors sets a stimulus and depolarization threshold. Weaker stimuli, which activate VDCCs, often lead to the induction of LTD (Zucker 1999). LTD also requires the activation of group I mGluRs at many synapses and the subsequent activation of nitric oxide synthetase (Daniel et al. 1998). VDCCs can augment the NMDA Ca2+ signal if back-propagating action potentials precede activation of NMDA receptors (Zucker 1999). This receptor based scheme depends on the parameters of the Ca2+ signal, and thus examples of NMDA receptor- dependent LTD and mGluR-dependent LTP also exist (Nicoll et al. 1998).

The mechanisms used to induce synaptic plasticity in adult animals often follow the same pathways utilized for development and growth in the nervous system. Phosphorylation plays a critical role in LTP and it is triggered by Ca2+ influx ( Soderling and Derkach 2000). Ca2+ activation of Ca2+ / CaM kinase and Ca2+ activation of the Ras MAPK pathways play distinct roles in the maintenance phase of LTP. Autophosphorylation of Ca2+ /CaM kinase makes it Ca2+ independent and creates a mechanism for maintaining long-term phosphorylation. Active Ca2+/CaM kinase increases AMPA receptor responses and may be involved in the unmasking of silent receptors and the trafficking of new receptors to the extracellular membrane (Malinow et al. 2000, Soderling and Derkach 2000). Keeping Ca2+ /CaM kinase phosphorylated and active is opposed by the activity of protein phosphatase I. Herein lies another critical step in LTP: inhibiting protein phosphates. Phosphatase inhibition is mediated by Ca2+ activation of adenlyate cyclase, activation of PKA, and phosphorylation of inhibitor 1 (I1). I1 shuts off protein phosphatase I and Ca2+ /CaM kinase thus stays phosphorylated and active (Soderling and Derkach 2000). Another critical component of LTP expression is protein production. Ca2+ /CaM kinase is also implicated in gene expression as well as Ca2+-activation of Ras/MAPK and, just like observed developmentally, phosphorylation of CREB (Platenik et al. 2000). Another similarity to development is the clear involvement of neurotrophins in LT P expression. Neurotrophins directly modulate Ca2+ physiology and they activate the Ras MAPK pathway (McAllister et al. 1999, Klintsova and Greenough 1999).

4. Ca2+ In Aging And Degeneration

The role of Ca2+ in development and plasticity requires flawless control over its intracellular concentration. Aging in the brain, and in many other tissues, occurs in part through a disruption in the ability to maintain Ca2+ homeostasis (Thibault et al. 1998). A system level theory for explaining aging poses that chronic exposure to glucocorticoid stress hormones creates a disruption of Ca2+ homeostasis (Thibault et al. 1998). In the hippocampus, stress hormones and/or aging increases the expression of L-type Ca2+ channels (Thibault et al. 1998). The increased Ca2+ signal suppresses hippocampal neuron activity by stimulating Ca2+ -activated K+ channels and, consequently, the hippocampus becomes less effective in its role of terminating the stress response. Circulating levels of stress hormones therefore progressively increase over an animal’s lifetime and consequently the deleterious effects of Ca2+ overload also become progressively worse. Elevated Ca2+ in aged neurons is proposed to create dysfunctional plasticity and to reduce the threshold for Ca2+ -mediated cell death.

Disruption of Ca2+ homeostasis is also proposed to be a critical event in apoptosis and necrosis produced in many age-related neurodegenerative disorders (Mattson 1998, Mattson et al. 2000, Thibault et al. 1998). Periods of excessive excitation, as might occur during stroke or in response to β-amyloid stimulation, cause abnormally high levels of Ca + ions to enter the cell. The candid ate mechanisms for the pathological increase in Ca2+ influx include VDCCs, NMDA receptor gated channels, and mGluR activation and downstream release of Ca2+ from internal stores. The consequent Ca2+ overload stimulates Ca2+ -sensitive proteases and it plays a significant role in the generation of reactive oxygen species (ROS) (Ma ttson et al. 2000). High levels of cytoplasmic Ca2+ cause mitochondrial Ca2+ loading which stimulates mitochondrial ROS production and release of apoptotic factors (Mattson 19 98).

The flood of Ca2+ triggers abnormal activation of calpain and free radicals activate caspases, both of which are viewed to create excessive proteolysis. In addition, Ca2+ sequestration by mitochondria during excessive excitation reduces the production of ATP with a critical cost of shutting down ATPases responsible for maintaining the cell’s membrane potential (Albin and Greenamyre 1992). Plasma membrane Na+ K+-ATPases require huge amounts of energy and their reduced activity leads to cellular depolarization , activation of VDCCs, and the removal of Mg + voltage-dependent block from NMDA gated channels.

Ca2+ also triggers cytoplasmic production of ROS through the activation of Ca2+ -dependent enzymes. Ca2+ -activated proteases convert xanthine dehydrogenase into xanthine oxidase which produces superoxide anions and H O . High levels of cytoplasmic Ca2+ triggered by NMDA receptor activation also activate nitric oxide synthetase (NOS). NO produced by the activation of NOS is a free radical, as well as a ubiquitous mediator of biological processes (Dawson and Dawson 1998). NO turns into a much more potent oxidant, however, after it reacts with the superoxide anion under conditions of oxidative stress to produce highly reactive peroxynitrite. The ROS generated by these mechanisms cause lipid, protein, and nucleic acid oxidation and ultimately cell death.


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