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The Drosophila neuropeptide, DPKQDFMRFamide, was previously shown to enhance excitatory junctional potentials (EJPs) and muscle contraction by both presynaptic and postsynaptic actions. Since the peptide acts on both sides of the synaptic cleft, it has been difficult to examine postsynaptic modulatory mechanisms, particularly when contractions are elicited by nerve stimulation. Here, postsynaptic actions are examined in 3rd instar larvae by applying peptide and the excitatory neurotransmitter, L-glutamate, in the bathing solution to elicit contractions after silencing motor output by removing the central nervous system (CNS). DPKQDFMRFamide enhanced glutamate-evoked contractions at low concentrations (EC50 1.3 nM), consistent with its role as a neurohormone, and the combined effect of both substances was supra-additive. Glutamate-evoked contractions were also enhanced when transmitter release was blocked in temperature-sensitive (Shibire) mutants, confirming the peptide's postsynaptic action. The peptide increased membrane depolarization in muscle when co-applied with glutamate, and its effects were blocked by nifedipine, an L-type channel blocker, indicating effects at the plasma membrane involving calcium influx. DPKQDFMRFamide also enhanced contractions induced by caffeine in the absence of extracellular calcium, suggesting increased calcium release from the sarcoplasmic reticulum (SR) or effects downstream of calcium release from the SR. The peptide's effects do not appear to involve calcium/calmodulin-dependent protein kinase II (CaMKII), previously shown to mediate presynaptic effects. The approach used here might be useful for examining postsynaptic effects of neurohormones and cotransmitters in other systems. [ABSTRACT FROM AUTHOR]

Shank is a post-synaptic scaffolding protein that has many binding partners. Shank mutations and copy number variations (CNVs) are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. It is not known which Shank binding partners are responsible for these defects. Here we show that the C. elegans SHN-1/Shank binds L-type calcium channels and that increased and decreased shn-1 gene dosage alter L-channel current and activity-induced expression of a CRH-1/CREB transcriptional target (gem-4 Copine), which parallels the effects of human Shank copy number variations (CNVs) on Autism spectrum disorders and schizophrenia. These results suggest that an important function of Shank proteins is to regulate L-channel current and activity induced gene expression.

Background: Recent examination of the STEADY‐PD III isradipine clinical trial data concluded that early‐stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. Objectives: To test this hypothesis, the data from the STEADY‐PD II isradipine clinical trial, in which an extended‐release (ER) formulation of the drug was used, was re‐examined. Methods: The re‐analysis of the STEADY‐PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52‐week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. Results: Participant cohorts were well‐matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. Conclusions: These results are consistent with the recent secondary analysis of the STEADY‐PD III clinical trial—suggesting that clinically attainable brain exposure to isradipine may slow early‐stage PD progression. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

L‐type voltage‐gated calcium channels are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major L‐type voltage‐gated calcium channel isoforms in the brain is CaV1.3. Mice lacking CaV1.3 are reported to have impairments in fear conditioning and depressive‐like behaviors, which have been linked to CaV1.3 function in the hippocampus and amygdala. Genetic variation in CaV1.3 has been linked to a variety of psychiatric disorders, including autism and schizophrenia, which are associated with altered motor learning, associative learning and social function. Here, we explored whether CaV1.3 plays a role in these behaviors. We found that CaV1.3 knockout mice have deficits in rotarod learning despite normal locomotor function. Deletion of CaV1.3 is also associated with impaired gait adaptation and associative learning on the Erasmus Ladder. We did not observe any impairments in CaV1.3 knockout mice on assays of anxiety‐like, depression‐like or social preference behaviors. Our results suggest an important role for CaV1.3 in neural circuits involved in motor learning and concur with previous data showing its involvement in associative learning. [ABSTRACT FROM AUTHOR]

Abstract Perioperative sleep disturbance is a risk factor for persistent pain after surgery. Clinical studies have shown that patients with insufficient sleep before and after surgery experience more intense and long-lasting postoperative pain. We hypothesize that sleep deprivation alters L-type calcium channels in the dorsal root ganglia (DRG), thus delaying the recovery from post-surgical pain. To verify this hypothesis, and to identify new predictors and therapeutic targets for persistent postoperative pain, we first established a model of postsurgical pain with perioperative sleep deprivation (SD) by administering hind paw plantar incision to sleep deprivation rats. Then we conducted behavioral tests, including tests with von Frey filaments and a laser heat test, to verify sensory pain, measured the expression of L-type calcium channels using western blotting and immunofluorescence of dorsal root ganglia (an important neural target for peripheral nociception), and examined the activity of L-type calcium channels and neuron excitability using electrophysiological measurements. We validated the findings by performing intraperitoneal injections of calcium channel blockers and microinjections of dorsal root ganglion cells with adeno-associated virus. We found that short-term sleep deprivation before and after surgery increased expression and activity of L-type calcium channels in the lumbar dorsal root ganglia, and delayed recovery from postsurgical pain. Blocking these channels reduced impact of sleep deprivation. We conclude that the increased expression and activity of L-type calcium channels is associated with the sleep deprivation-mediated prolongation of postoperative pain. L-type calcium channels are thus a potential target for management of postoperative pain.

Perioperative sleep disturbance is a risk factor for persistent pain after surgery. Clinical studies have shown that patients with insufficient sleep before and after surgery experience more intense and long-lasting postoperative pain. We hypothesize that sleep deprivation alters L-type calcium channels in the dorsal root ganglia (DRG), thus delaying the recovery from post-surgical pain. To verify this hypothesis, and to identify new predictors and therapeutic targets for persistent postoperative pain, we first established a model of postsurgical pain with perioperative sleep deprivation (SD) by administering hind paw plantar incision to sleep deprivation rats. Then we conducted behavioral tests, including tests with von Frey filaments and a laser heat test, to verify sensory pain, measured the expression of L-type calcium channels using western blotting and immunofluorescence of dorsal root ganglia (an important neural target for peripheral nociception), and examined the activity of L-type calcium channels and neuron excitability using electrophysiological measurements. We validated the findings by performing intraperitoneal injections of calcium channel blockers and microinjections of dorsal root ganglion cells with adeno-associated virus. We found that short-term sleep deprivation before and after surgery increased expression and activity of L-type calcium channels in the lumbar dorsal root ganglia, and delayed recovery from postsurgical pain. Blocking these channels reduced impact of sleep deprivation. We conclude that the increased expression and activity of L-type calcium channels is associated with the sleep deprivation-mediated prolongation of postoperative pain. L-type calcium channels are thus a potential target for management of postoperative pain. [ABSTRACT FROM AUTHOR]

Shank is a post-synaptic scaffolding protein that has many binding partners. Shank mutations and copy number variations (CNVs) are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. It is not known which Shank binding partners are responsible for these defects. Here we show that the C. elegans SHN-1/Shank binds L-type calcium channels and that increased and decreased shn-1 gene dosage alter L-channel current and activity-induced expression of a CRH-1/CREB transcriptional target (gem-4 Copine), which parallels the effects of human Shank copy number variations (CNVs) on Autism spectrum disorders and schizophrenia. These results suggest that an important function of Shank proteins is to regulate L-channel current and activity induced gene expression.

Behaviorally adequate neuronal firing patterns are critically dependent on the specific types of ion channel expressed and on their subcellular localization. This study combines in situ electrophysiology with genetic and pharmacological intervention in larval Drosophila melanogaster of both sexes to address localization and function of L-type like calcium channels in motoneurons. We demonstrate that Dmca 1D (Cavl homolog) L-type like calcium channels localize to both the somatodendritic and the axonal compartment of larval crawling motoneurons. In situ patch-clamp recordings in genetic mosaics reveal that DmcalD channels increase burst duration and maximum intraburst firing frequencies during crawling-like motor patterns in semi-intact animals. Genetic and acute pharmacological manipulations suggest that prolonged burst durations are caused by dendritically localized Dmcal D channels, which activate upon cholinergic synaptic input and amplify EPSPs, thus indicating a conserved function of dendritic L-type channels from Drosophila to vertebrates. By contrast, maximum intraburst firing rates require axonal calcium influx through DmcalD channels, likely to enhance sodium channel de-inactivation via a fast afterhyperpolarization through BK channel activation. Therefore, in unmyelinated Drosophila motoneurons different functions of axonal and dendritic L-type like calcium channels likely operate synergistically to maximize firing output during locomotion. [ABSTRACT FROM AUTHOR]

Many cellular events including electrical activity and muscle contraction are regulated and coordinated by intracellular concentration ([]. In detrusor smooth muscle (DSM) cells, []i is normally maintained at very low levels and rises transiently during signalling processes as a result of (i) influx from the extracellular space (mainly via L-type and T-type channels) and (ii) release from sarcoplasmic reticulum (SR) into the cytoplasm. Intracellular buffers, both fixed and diffusible, play a vital role in shaping the radial distribution of free . Our aim, in the work presented here, is to develop a mathematical model of buffering and diffusion and to generate transient in guinea pig DSM cells. The transient is generated using inward current that arises following voltage clamp and mediated by L-type and T-type channels. transient is obtained for different radial locations (or shells) of the DSM cytosol. This modeling study explores the levels of []i achieved near the plasma membrane and in deeper locations. The transient generated in our model shows a high degree of similarity with experimental findings in terms of amplitude, duration and half-decay time. A number of different buffer properties such as concentration and mobility are tested for their effect on amplitude and shape of transient. The presence of fast buffer concentration in the cytosol markedly delays the rise of []i in the core of the cell. Increase in the mobility of fast buffer slightly speeds up the redistribution of . To explore the model further, the role of plasma membrane -ATPase (PMCA) pump, sarcoplasmic/endoplasmic reticulum -ATPase (SERCA) pump and sodium calcium exchanger (NCX) on transient is studied and it is suggested that NCX may be of primary importance for the immediate lowering of []i during the falling phase of a transient in DSM cells. [ABSTRACT FROM AUTHOR]

D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, this study assessed the calcium-dependence and drug-induced plasticity of D2S and D2L receptor-dependent G protein-coupled inwardly rectifying potassium (GIRK) currents. The results reveal that D2S, but not D2L receptors, exhibited calcium-dependent desensitization similar to that exhibited by endogenous autoreceptors. Two pathways of calcium signaling that regulated D2 autoreceptor-dependent GIRK signaling were identified, which distinctly affected desensitization and the magnitude of D2S and D2L receptor-dependent GIRK currents. Previous in vivo cocaine exposure removed calcium-dependent D2 autoreceptor desensitization in wild type, but not D2S-only mice. Thus, expression of D2S as the exclusive autoreceptor was insufficient for cocaine-induced plasticity, implying a functional role for the co-expression of D2S and D2L autoreceptors.

We tested several molecular and cellular mechanisms of cardiomyocyte contraction- relaxation function that could account for the reduced systolic and enhanced diastolic function observed with exposure to extracellular Zn2+. Contraction-relaxation function was monitored in isolated rat and mouse cardiomyocytes maintained at 37°C, stimulated at 2 or 6 Hz, and exposed to 32 μM Zn2+ or vehicle. Intracellular Zn2+ detected using FluoZin-3 rose to a concentration of ~13 nM in 3-5 min. Peak sarcomere shortening was significantly reduced and diastolic sarcomere length was elongated after Zn2+ exposure. Peak intracellular Ca2+ detected by Fura-2FF was reduced after Zn2+ exposure. However, the rate of cytosolic Ca2+ decline reflecting sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity and the rate of Na/Ca2+ exchanger activity evaluated by rapid Na- induced Ca2+ efflux were unchanged by Zn2+ exposure. SR Ca2+ load evaluated by rapid caffeine exposure was reduced by ~50%, and L-type calcium channel inward current measured by whole cell patch clamp was reduced by ~70% in cardiomyocytes exposed to Zn2+. Furthermore, ryanodine receptor (RyR) S2808 and phospholamban (PLB) S16/T17 were markedly dephosphorylated after perfusing hearts with 50 μM Zn2+. Maximum tension development and thinfilament Ca2+ sensitivity in chemically skinned cardiac muscle strips were not affected by Zn2+ exposure. These findings suggest that Zn2+ suppresses cardiomyocyte systolic function and enhances relaxation function by lowering systolic and diastolic intracellular Ca2+ concentrations due to a combination of competitive inhibition of Ca2+ influx through the L-type calcium channel, reduction of SR Ca2+ load resulting from phospholamban dephosphorylation, and lowered SR Ca2+ leak via RyR dephosphorylation. The use of the low-Ca2+- affinity Fura-2FF likely prevented the detection of changes in diastolic Ca2+ and SERCA2a function. Other strategies to detect diastolic Ca2+ in the presence of Zn2+ are essential for future work. [ABSTRACT FROM AUTHOR]

Abstract: Voltage-gated calcium channels (VGCC) are involved in a large variety of cellular Ca2+ signaling processes, including exocytosis, a Ca2+ dependent release of neurotransmitters and hormones. Great progress has been made in understanding the mode of action of VGCC in exocytosis, a process distinguished by two sequential yet independent Ca2+ binding reactions. First, Ca2+ binds at the selectivity filter, the EEEE motif of the VGCC, and second, subsequent to a brief and intense Ca2+ inflow to synaptotagmin, a vesicular protein. Inquiry into the functional and physical interactions of the channels with synaptic proteins has demonstrated that exocytosis is triggered during the initial Ca2+ binding at the channel pore, prior to Ca2+ entry. Accordingly, a cycle of secretion begins by an incoming stimulus that releases vesicles from a releasable pool upon Ca2+ binding at the pore, and at the same time, the transient increase in [Ca2+]i primes a fresh set of non-releasable vesicles, to be fused by the next incoming stimulus. We propose a model, in which the Ca2+ binding at the EEEE motif and the consequent conformational changes in the channel are the primary event in triggering secretion, while synaptotagmin acts as a vesicle docking protein. Thus, the channel serves as the molecular On/Off signaling switch, where the predominance of a conformational change in Ca2+-bound channel provides for the fast secretory process. [ABSTRACT FROM AUTHOR]

Abstract: L-type Ca2+ channels are mediators of Ca2+ influx and the regulatory events accompanying it and are pivotal in the function and dysfunction of ventricular cardiac myocytes. L-type Ca2+ channels are located in sarcolemma, including the T-tubules facing the sarcoplasmic reticulum junction, and are activated by membrane depolarization, but intracellular Ca2+-dependent inactivation limits Ca2+ influx during action potential. I CaL is important in heart function because it triggers excitation–contraction coupling, modulates action potential shape and is involved in cardiac arrhythmia. L-type Ca2+ channels are multi-subunit complexes that interact with several molecules involved in their regulations, notably by β-adrenergic signaling. The present review highlights some of the recent findings on L-type Ca2+ channel function, regulation, and alteration in acquired pathologies such as cardiac hypertrophy, heart failure and diabetic cardiomyopathy, as well as in inherited arrhythmic cardiac diseases such as Timothy and Brugada syndromes. [Copyright &y& Elsevier]

Abstract: Store-operated Ca2+ channels (SOCs) are considered to be the principal route of Ca2+ influx in non-excitable cells. We have previously shown that in mast cells IgE+antigen (Ag) induces a dihydropyridine (DHP)-sensitive Ca2+ influx independently of Ca2+ store depletion. Since the DHP receptor is the α subunit of L-type Ca2+ channels (LTCCs), we examined the possible role of LTCCs in mast cell activation. Mast cells exhibited substantial expression of the α1C (CaV1.2) subunit mRNA and protein on their cell surface. IgE+Ag-induced Ca2+ influx was substantially reduced by the LTCC inhibitor nifedipine, and enhanced by the LTCC activator (S)-BayK8644, whereas these agents had minimal effects on thapsigargin (TG)-induced Ca2+ influx. These LTCC-modulating agents regulated IgE+Ag-induced cell activation but not TG-induced cell activation. Inhibition of SOCs by 2-aminoethoxydiphenyl borate reduced both degranulation and production of cytokines, including interleukin-13 and tumor necrosis factor-α, whereas LTCC modulation reciprocally regulated degranulation and cytokine production. IgE+Ag, but not TG, induced substantial plasma membrane depolarization, which stimulated a DHP-sensitive Ca2+ response. Moreover, IgE+Ag-, but not TG-induced mitochondrial Ca2+ increase was regulated by LTCC modulators. Finally, gene silencing analyses using small interfering RNA revealed that the α1C (CaV1.2) LTCC mediated the pharmacological effects of the LTCC-modulating agents. These results demonstrate that mast cells express LTCCs, which becomes activated by membrane depolarization to regulate cytosolic and mitochondrial Ca2+, thereby controlling mast cell activation in a distinct manner from SOCs. [Copyright &y& Elsevier]

Endurance exercise is widely assumed to improve cardiac function in humans, but the mechanisms involved in such changes are not clearly understood. The purpose of this study is to determine whether training elicits adaptations at the level of the L-type Ca(2+) channel. Sprague-Dawley rats performed swimming training at either moderate intensity (MOD) or high intensity (HIGH) during 8 weeks. The trained rats were studied by echocardiography and the whole-cell L-type Ca(2+) currents (I (Ca,L)) characteristics in a single cell were measured by standard whole-cell patch-clamp recording technique. Echocardiography showed that septal and posterior wall thickness in MOD and HIGH increased with the increased LV mass by 43 and 41%, respectively (P < 0.05). Training (P < 0.05) increased mean myocyte capacitance (approximately 38% in MOD and HIGH) and myocyte length (approximately 20% longer in MOD and 26% longer in HIGH), thus providing electrophysiological and morphological evidence that the training elicited LV cardiocyte hypertrophy. Mean peak I (Ca,L) was not different in three groups. However, whole-cell I (Ca,L) density was decreased in MOD and HIGH versus sedentary (P < 0.05), but there was no significant difference between MOD and HIGH. The present study provides the evidence of a training adaptation in intrinsic I (Ca,L) characteristics in ventricular myocardium, which demonstrates a remarkable adaptive plasticity of L-type channel characteristics in training rat heart. [ABSTRACT FROM AUTHOR]

Active Ca2+ absorption through epithelial Ca2+ channels TRPV5/6 in duodenum is activated by hyperpolarisation. However, when diet and Ca2+ are plentiful, digestion products cause depolarisation. We therefore used homology-based PCR from a rat jejunal mucosal cDNA preparation to reveal the presence of the neuroendocrine L-type isoform Cav1.3α1. Immunocytochemical labelling and immunoblotting localised Cav1.3α1 protein in apical membrane from proximal jejunum to mid ileum. Perfusion studies in vivo with 1.25 mM luminal Ca2+ revealed L-type channel activity. Inhibition of glucose absorption with phloridzin strongly inhibited 45Ca2+ absorption; absorption was inhibited by nifedipine and Mg2+ and activated by Bay K 8644, none of which affect TRPV5/6. At 10 mM Ca2+, nifedipine inhibited 45Ca2+ absorption with a time course similar to that at 1.25 mM Ca2+: absorption was therefore channel-mediated rather than paracellular. We suggest that in times of dietary sufficiency, Cav1.3 may mediate a significant route of Ca2+ absorption into the body. [Copyright &y& Elsevier]

In mature B cells engagement of the antigen-receptor (BCR) results in a peak of Ca2+ from mobilisation of internal stores followed by a lower but sustained elevation that is dependent upon extracellular Ca2+. The Ca2+ channel involved in the sustained elevation remains uncharacterised. Here we have presented evidence that although non-excitable, B cells expressed a BCR-activated Ca2+ channel sharing some properties of conventional L-type voltage-gated channels. Human lymphoma B cells expressed a transcript having homology to a highly conserved region on the pore-forming α1.2 subunit of L-type voltage-gated Ca2+ channels. The α1.2 protein was expressed together with the β1 subunit, while an antibody raised against the extracellular portion of L-type Ca2+ channels caused a Ca2+ flux in these cells. Drugs that block classical L-type channels abolished the BCR-induced Ca2+ flux while directly activating a plasma membrane Ca2+ channel: activation of the channel, separate from Ca2+ influx, inhibited BCR-induced Ca2+ release from intracellular stores. BAYK8644—a drug that binds to open L-type channels—failed to release intracellular Ca2+ in the absence of BCR cross-linking but instantly abolished the BCR-induced Ca2+ peak and established the sustained phase of the response. The BCR-activated calcium channel appeared to terminate the initial peak of BCR-induced Ca2+ release and initiate the sustained phase of the signal. [Copyright &y& Elsevier]

17β-estradiol induces rapid effects on cells of the immune system via plasma membrane surface receptor but the ways in which delayed signals involving intracellular receptors affect the same functions are not well understood. To study the delayed but sustained events in estradiol signaling, we have investigated macrophage Ca2+ signaling, detected specific Ca2+ ion channel activated and found a relationship between intracellular calcium [Ca2+]i and macrophage release of reactive oxygen species (ROS) and nitric oxide (NO) during delayed 17β-estradiol activity. We found evidence of additional effect of estradiol on capacitative entry of Ca2+, Ca2+ entry through L-type channel and a direct relationship between [Ca2+]i and generation of ROS and NO. This study demonstrates that 17β-estradiol exhibits a delayed phase of Ca2+ influx involving L-type channel and regulates macrophage immune redox function. [Copyright &y& Elsevier]

We assessed the effect of nimodipine, an L-type calcium channel blocker, on the escape deficit induced by prior exposure to inescapable shock in rats in four experiments. In Experiment 1, we injected rats at each of three time points (i.e., before shock exposure, after shock exposure, and before shuttle escape testing) with one of four doses of nimodipine (0, 0.5, 2.5, 5.0 mg/kg). The 5.0-mg/kg dose was most effective, acting to reduce shuttle escape latencies of inescapably shocked rats to a level comparable with nonshocked controls. No benefit occurred in Experiment 2, however, when nimodipine was administered at only one of the three time points used in the first experiment. Moreover, escape performance did not improve when rats received injections of nimodipine on the 2 days prior the experiment, and then one additional injection at one of the three time points identified above in Experiment 3. Finally, administration of nimodipine at two of the three time points did improve escape responding, but only when injected immediately prior both to shock exposure and the shuttle escape test. [Copyright &y& Elsevier]

The effects of phorbol esters on Ca channel currents in human neuroblastoma SH-SY5Y cells were studied using whole-cell patch-clamp recordings. Bath application of 12- O-tetradecanoylphorbol-13-acetate (TPA) or phorbol 12,13-dibutyrate (PDBu; 100 nM to 1 μM), known activators of protein kinase C (PKC), enhanced Ca channel currents in a voltage-dependent manner similar to that of Bay K 8644. TPA also enhanced Ca channel currents during cell dialysis with the PKC pseudosubstrate, PKC(19-36), and in cells which had been pre-incubated with 500 nM staurosporine, and which were exposed to staurosporine during recordings. Application of 4 α-phorbol12, 13-didecanoate (4 α-PDD; 100 nM), which does not activate PKC, caused current enhancement similar to the effects of TPA. However, intracellular dialysis of TPA was without effect on Ca channel currents. Residual Ca channel currents recorded after exposure to 1 μM ω-conotoxin GVIA were still enhanced by TPA, but in the presence of either Bay K 8644 (5 μM) or nifedipine (5 μM), TPA was without effect. When cells were pre-incubated for 10 min at 37° C with 100 nM TPA, currents subsequently recorded in its absence were enhanced as compared to untreated cells; 5 μM nifedipine still inhibited currents to the same degree. This enhancement was not mimicked by 4 αPDD, and was inhibited by staurosporine. Our results indicate that acute applications of phorbol esters (at concentrations commonly used to activate PKC) enhance L-type Ca channel currents in SH-SY5Y cells via a PKC-independent mechanism which appears similar to that induced by Bay K 8644. By contrast, pre-incubation with TPA enhances both L- and N-type currents via activation of PKC. [ABSTRACT FROM AUTHOR]

Introduction : Calcium channel blockers (CCBs) comprise a heterogeneous group of medications that reduce calcium influx and attenuate cellular hyperactivity. Evidence of hyperactive intracellular calcium ion signaling in multiple peripheral cells of patients with bipolar disorder, calcium antagonist actions of established mood stabilizers, and a relative dearth of treatments have prompted research into potential uses of CCBs for this common and disabling condition. Areas covered : This review provides a comprehensive overview of intracellular calcium signaling in bipolar disorder, structure and function of calcium channels, pharmacology of CCBs, evidence of efficacy of CCBs in bipolar disorder, clinical applications, and directions for future research. Expert opinion : Despite mixed evidence of efficacy, CCBs are a promising novel approach to a demonstrated cellular abnormality in both poles of bipolar disorder. Potential advantages include low potential for sedation and weight gain, and possible usefulness for pregnant and neurologically impaired patients. Further research should focus on markers of a preferential response, studies in specific bipolar subtypes, development of CCBs acting preferentially in the central nervous system and on calcium channels that are primarily involved in neuronal signaling and plasticity.

We present a population density and moment-based description of the stochastic dynamics of domain [Formula: see text]-mediated inactivation of L-type [Formula: see text] channels. Our approach accounts for the effect of heterogeneity of local [Formula: see text] signals on whole cell [Formula: see text] currents; however, in contrast with prior work, e.g., Sherman et al. (Biophys J 58(4):985-995, 1990), we do not assume that [Formula: see text] domain formation and collapse are fast compared to channel gating. We demonstrate the population density and moment-based modeling approaches using a 12-state Markov chain model of an L-type [Formula: see text] channel introduced by Greenstein and Winslow (Biophys J 83(6):2918-2945, 2002). Simulated whole cell voltage clamp responses yield an inactivation function for the whole cell [Formula: see text] current that agrees with the traditional approach when domain dynamics are fast. We analyze the voltage-dependence of [Formula: see text] inactivation that may occur via slow heterogeneous domain [[Formula: see text]]. Next, we find that when channel permeability is held constant, [Formula: see text]-mediated inactivation of L-type channels increases as the domain time constant increases, because a slow domain collapse rate leads to increased mean domain [[Formula: see text]] near open channels; conversely, when the maximum domain [[Formula: see text]] is held constant, inactivation decreases as the domain time constant increases. Comparison of simulation results using population densities and moment equations confirms the computational efficiency of the moment-based approach, and enables the validation of two distinct methods of truncating and closing the open system of moment equations. In general, a slow domain time constant requires higher order moment truncation for agreement between moment-based and population density simulations.