L-Type Calcium Channels Mediate Calcium Oscillations in Early Postnatal Purkinje Neurons
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Ca2+ signaling is important in many fundamental neuronal processes including neurotransmission, synaptic plasticity, neuronal development, and gene expression. In cerebellar Purkinje neurons, Ca2+ signaling has been studied primarily in the dendritic region where increases in local Ca2+ have been shown to occur with both synaptic events and spontaneous electrical activity involving P-type voltage-gated Ca2+ channels (VGCCs), the predominant VGCC expressed by Purkinje neurons. Here we show that Ca2+ signaling is also a prominent feature of immature Purkinje neurons at developmental stages that precede expression of dendritic structure and involves L-type rather than P-type VGCCs. Immature Purkinje neurons acutely dissociated from postnatal day 4–7 rat pups exhibit spontaneous cytoplasmic Ca2+ oscillations. The Ca2+oscillations require entry of extracellular Ca2+, are blocked by tetrodotoxin, are communicated to the nucleus, and correlate closely with patterns of endogenously generated spontaneous and evoked electrical activity recorded in the neurons. Immunocytochemistry showed that L-, N-, and P/Q-types of VGCCs are present on the somata of the Purkinje neurons at this age. However, only the L-type VGCC antagonist nimodipine effectively antagonized the Ca2+ oscillations; inhibitors of P/Q and N-type VGCCs were relatively ineffective. Release of Ca2+from intracellular Ca2+ stores significantly amplified the Ca2+ signals of external origin. These results show that a somatic signaling pathway that generates intracellular Ca2+ oscillations and involves L-type VGCCs and intracellular Ca2+ stores plays a prominent role in the Ca2+ dynamics of early developing Purkinje neurons and may play an important role in communicating developmental cues to the nucleus.Keywords:
Tetrodotoxin
T-type calcium channels are low voltage-activated calcium channels that evoke small and transient calcium currents.Recently, T-type calcium channels have been implicated in neurodevelopmental disorders such as autism spectrum disorder and neural tube defects.However, their function during embryonic development is largely unknown.Here, we investigated the function and expression of T-type calcium channels in embryonic neural progenitor cells (NPCs).First, we compared the expression of T-type calcium channel subtypes (CaV3.1,3.2, and 3.3) in NPCs and differentiated neural cells (neurons and astrocytes).We detected all subtypes in neurons but not in astrocytes.In NPCs, CaV3.1 was the dominant subtype, whereas CaV3.2 was weakly expressed, and CaV3.3 was not detected.Next, we determined CaV3.1 expression levels in the cortex during early brain development.Expression levels of CaV3.1 in the embryonic period were transiently decreased during the perinatal period and increased at postnatal day 11.We then pharmacologically blocked T-type calcium channels to determine the effects in neuronal cells.The blockade of T-type calcium channels reduced cell viability, and induced apoptotic cell death in NPCs but not in differentiated astrocytes.Furthermore, blocking T-type calcium channels rapidly reduced AKT-phosphorylation (Ser473) and GSK3β-phosphorylation (Ser9).Our results suggest that T-type calcium channels play essential roles in maintaining NPC viability, and T-type calcium channel blockers are toxic to embryonic neural cells, and may potentially be responsible for neurodevelopmental disorders.
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T-type calcium channels are low-threshold voltage-gated calcium channel and characterized by unique electrophysiological properties such as fast inactivation and slow deactivation kinetics. All subtypes of T-type calcium channel (Cav3.1, 3.2 and 3.3) are widely expressed in the central nerve system, and they have an important role in homeostasis of sleep, pain response, and development of epilepsy. Recently, several reports suggest that T-type calcium channels may mediate neuronal plasticity in the mouse brain. We succeeded to develop T-type calcium channel enhancer ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate (SAK3) which enhances Cav3.1 and 3.3 currents in each-channel expressed neuro2A cells. SAK3 can promote acetylcholine (ACh) release in the mouse hippocampus via enhancing T-type calcium channel. In this review, we have introduced the role of T-type calcium channel, especially Cav3.1 channel in the mouse hippocampus based on our previous data using SAK3 and Cav3.1 knockout mice.
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Several types of calcium channels found in the central nervous system are possible participants in triggering neurotransmitter release. Synaptic transmission between hippocampal CA3 and CA1 neurons was mediated by N-type calcium channels, together with calcium channels whose pharmacology differs from that of L- and P-type channels but resembles that of the Q-type channel encoded by the α 1A subunit gene. Blockade of either population of channels strongly increased enhancement of synaptic transmission with repetitive stimuli. Even after complete blockade of N-type channels, transmission was strongly modulated by stimulation of neurotransmitter receptors or protein kinase C. These findings suggest a role for α 1A subunits in synaptic transmission and support the idea that neurotransmitter release may depend on multiple types of calcium channels under physiological conditions.
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Voltage-gated calcium channels are found in the plasma membrane of many excitable and non-excitable cells. When open, they permit influx of calcium, which acts as a second messenger to initiate diverse physiological cellular processes. Ten unique α 1 subunits, grouped in three families (CaV1, CaV2, and CaV3), encode biophysically and pharmacologically distinct low-voltage-activated T-type and high-voltage-activated L-type, N-type, P/Q-type, and R-type calcium channels. T-type calcium channels are found in neurons where they generate low-threshold calcium spikes and influence action potential firing patterns, in heart cells where they influence pacemaking and impulse conduction, in smooth muscle cells where they regulate myogenic tone and proliferation, in endocrine cells where they regulate hormone secretion, and in sperm where they regulate the acrosome reaction. Validation of T-type calcium channels in disease is based on an abundance of data pertaining to clinical efficacy of T-type calcium channel blockers in certain human conditions as well as information relating to the distribution, functional properties, and physiological roles of these channels. This review focuses on the cellular and molecular pharmacology of T-type calcium channels. It describes novel research approaches to discover potent and selective T-type calcium channel modulators as potential drugs for treating human disease and as tools for understanding better the physiological roles of T-type calcium channels.
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Voltage-gated calcium channels are important for the depolarization-evoked contraction of vascular smooth muscle cells (SMCs), with L-type channels being the classical channel involved in this mechanism. However, it has been demonstrated that the CaV2.1 subunit, which encodes a neuronal isoform of the voltage-gated calcium channels (P/Q-type), is also expressed and contributes functionally to contraction of renal blood vessels in both mice and humans. Furthermore, preglomerular vascular SMCs and aortic SMCs coexpress L-, P-, and Q-type calcium channels within the same cell. Calcium channel blockers are widely used as pharmacological treatments. However, calcium channel antagonists vary in their selectivity for the various calcium channel subtypes, and the functional contribution from P/Q-type channels as compared with L-type should be considered. Confirming the presence of P/Q-type voltage-gated calcium channels in other types of vascular SMCs could be important when investigating phenomena such as hypertension, migraine, and other diseases known to involve SMCs and voltage-gated calcium channels. The purpose of this review was to give a short overview of the possible roles of P/Q-type calcium channels within the vascular system with special focus on the renal vasculature.
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The early studies of cardiac and smooth muscle cells provided evidence for two different calcium channels, the L-type (also called high-voltage activated [HVA]) and T-type (low-voltage activated [LVA]). These calcium channels provided calcium for muscle contractions and pace-making activities. As might be expected, the number of different calcium channels increased when researchers studied neurons and the identification of the neuronal calcium channels has proven to be much more difficult than with the muscle calcium channels. There are two reasons for this difficulty; (1) a larger number of different calcium channels in neurons and (2) many of the different calcium channels have similar kinetic properties. This review uses the N-type calcium channel to illustrate the difficulties in identifying and characterizing calcium channels in neurons. It shows that the discovery of toxins that can specifically block single calcium channel types has made it possible to easily and rapidly discern the physiological roles of the different calcium channels in the neuron, Without these toxins it is unlikely that progress would have been as rapid.
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Calcium ions are the major signaling ions in the cells. They regulate muscle contraction, neurotransmitter secretion, cell growth and migration, and the activity of several proteins including enzymes and ion channels and transporters. They participate in various signal transduction pathways, thereby regulating major physiological functions. Calcium ion entry into the cells is regulated by specific calcium channels and transporters. There are mainly six types of calcium channels, of which only two are prominent in the heart. In cardiac tissues, the two types of calcium channels are the L type and the T type. L-type channels are found in all cardiac cells and T-type are expressed in Purkinje cells, pacemaker and atrial cells. Both these types of channels contribute to atrioventricular conduction as well as pacemaker activity. Given the crucial role of calcium channels in the cardiac conduction system, mutations and dysfunctions of these channels are known to cause several diseases and disorders. Drugs targeting calcium channels hence are used in a wide variety of cardiac disorders including but not limited to hypertension, angina, and arrhythmias. This review summarizes the type of cardiac calcium channels, their function, and disorders caused by their mutations and dysfunctions. Finally, this review also focuses on the types of calcium channel blockers and their use in a variety of cardiac disorders.
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The properties of voltage-dependent calcium channels in muscle cells and neurons have been studied using the whole-cell patch clamp technique. Cardiac muscle cells, vascular muscle cells, and neurons all have multiple types of calcium channels, and the different types have different pharmacological properties. The predominant calcium current in most cardiac and vascular muscle cells is carried through L-type calcium channels, which are potently and completely blocked by dihydropyridine drugs; the block is voltage-dependent, and is more potent at depolarized holding potentials where the calcium current is partly inactivated. In neurons, much less of the high-threshold calcium channel current is blocked by dihydropyridines, because much of it is carried through N-type calcium channels, which are not blocked by dihydropyridines but are blocked by the peptide toxin omega-conotoxin GVIA. In addition to L-type and N-type calcium channels, rat neurons have a third type of high-threshold calcium channel that is not blocked by either omega-conotoxin or dihydropyridines. Some neurons also have a fourth type of calcium current, a low threshold current carried by T-type calcium channels.
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Abstract Voltage-gated calcium channels are important contributors to the transmission and processing of nociceptive information in the primary afferent pain pathway. Several types of calcium channels and their ancillary subunits are dysregulated in response to nerve injury or inflammation. Notably, calcium channels have emerged as prominent targets for analgesics. This article discusses the roles of specific types of voltage-gated calcium channels in the afferent pain pathway and their utility as pharmacological targets for therapeutic intervention in chronic pain. Several calcium channel subtypes are dysregulated during chronic pain conditions, giving rise to increased neuronal excitability and synaptic transmission. N-type calcium channels, Cav3.2 T-type calcium channels, and the Cavα2δ subunit are validated targets for the development and clinical use of small organic analgesics, with R-type channels showing potential as possible targets based on preclinical studies.
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