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Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population,...
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... is a new Ca 2 channel antagonist that ap- pears promising in the treatment of hypertension and angina pectoris [69]. Structurally ( Figure 5) and phar- macologically, it is clearly distinct from currently used Ca 2 channel antagonists. Its favorable pharmacologi- cal pro~le and limited side effects [69] could be related to blockade of T-type Ca 2 channels (in addition to L-type). Indeed, studies in guinea pig and rat myocytes indicate that mibefradil blocks T-type Ca 2 channels with 10 to 30-fold selectivity over L-type Ca 2 chan- nels [26,65,124,134]. Preliminary studies in rat hippo- campal CA 3 neurons also suggest that mibefradil blocks T-type Ca 2 channels selectively in these cells, but this compound has no neurological applications be- cause it does not cross the blood-brain ...
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... Most studies on EMF exposure are on the L-type calcium channels (long-lasting), whereas other types of calcium channels are sparsely studied. Particularly, the T-type calcium channels (transient) may deserve some attention, since they are sensitive to small changes in membrane potential [52] and could be more responsive to low-level EMF exposure [53]. ...
The way that living cells respond to non-ionizing electromagnetic fields (EMF), including static/extremely-low frequency and radiofrequency electromagnetic fields, fits the pattern of 'cellular stress response' - a mechanism manifest at the cellular level intended to preserve the entire organism. It is a set pattern of cellular and molecular responses to environmental stressors, such as heat, ionizing radiation, oxidation, etc. It is triggered by cellular macromolecular damage (in proteins, lipids, and DNA) with the goal of repairing and returning cell functions to homeostasis. The pattern is independent of the type of stressor encountered. It involves cell cycle arrest, induction of specific molecular mechanisms for repair, damage removal, cell proliferation, and cell death if damage is too great. This response could be triggered by EMF-induced alternation in oxidative processes in cells. The concept that biological response to EMF is a 'cellular stress response' explains many observed effects of EMF, such as nonlinear dose- and time-dependency, increased and decreased risks of cancer and neurodegenerative diseases, enhanced nerve regeneration, and bone healing. These responses could be either detrimental or beneficial to health, depending on the duration and intensity of the exposure, as well as specific aspects of the living organism being exposed. A corollary to electromagnetic hypersensitivity syndrome (EHS) could be an inappropriate response of the hippocampus/limbic system to EMF, involving glucocorticoids on the hypothalamic-pituitary-adrenal axis.
... The peak of ILVA and IHVA localized at ~-40 mV and ~-20 mV, respectively (Fig. 1C3), and the presence of the two current types yielded a wide range of responsive Vm. The first peak suggested the presence of T-type Ca 2+ channels because the typical T-type ICa reaches its maximal amplitude between -40 mV and -10 mV (Ertel et al., 1997). However, unlike T-type ICa in other tissues, ILVA was not fully inactivated at -39 mV, a potential that is close to the physiological Vm in darkness (-40 mV). ...
PURPOSE. Cone photoreceptors of the retina use a sophisticated ribbon-containing synapse to convert light-dependent changes in membrane potential into release of synaptic vesicles (SVs). We aimed to study the functional and structural maturation of mouse cone photoreceptor ribbon synapses during postnatal development and to investigate the role of the synaptic ribbon in SV release. METHODS. We performed patch-clamp recordings from cone photoreceptors and their postsynaptic partners, the horizontal cells during postnatal retinal development to reveal the functional parameters of the synapses. To investigate the occurring structural changes, we applied immunocytochemistry and electron microscopy. RESULTS. We found that immature cone photoreceptor terminals were smaller, they had fewer active zones (AZs) and AZ-anchored synaptic ribbons, and they produced a smaller Ca2+ current than mature photoreceptors. The number of postsynaptic horizontal cell contacts to synaptic terminals increased with age. However, tonic and spontaneous SV release at synaptic terminals stayed similar during postnatal development. Multiquantal SV release was present in all age groups, but mature synapses produced larger multiquantal events than immature ones. Remarkably, at single AZs, tonic SV release was attenuated during maturation and showed an inverse relationship with the appearance of anchored synaptic ribbons. CONCLUSIONS. Our developmental study suggests that the presence of synaptic ribbons at the AZs attenuates tonic SV release and amplifies multiquantal SV release. However, spontaneous SV release may not depend on the presence of synaptic ribbons or voltagesensitive Ca2+ channels at the AZs. Mammalian cone photoreceptors enable through their sophisticated synapse the high-fidelity transfer of visual information to second-order neurons in the retina. The synapse contains a proteinaceous organelle, called the synaptic ribbon, which tethers synaptic vesicles (SVs) at the active zone (AZ) close to voltage-gated Ca2+ channels. However, the exact contribution of the synaptic ribbon to neurotransmission is not fully understood, yet. In mice, precursors to synaptic ribbons appear within photoreceptor terminals shortly after birth as free-floating spherical structures, which progressively elongate and then attach to the AZ during the following days. Here, we took advantage of the process of synaptic ribbon maturation to study their contribution to SV release. We performed whole-cell patch-clamp recordings from cone photoreceptors at three postnatal (P) development stages (P8– 9, P12–13, >P30) and measured evoked SV release, SV replenishment rate, recovery from synaptic depression, domain organization of voltage-sensitive Ca2+ channels, and Ca2+-sensitivity of exocytosis. Additionally, we performed electron microscopy to determine the density of SVs at ribbon-free and ribbon-occupied AZs. Our results suggest that ribbon attachment does not organize the voltage-sensitive Ca2+ channels into nanodomains or control SV release probability. However, ribbon attachment increases SV density at the AZ, increases the pool size of readily releasable SVs available for evoked SV release, facilitates SV replenishment without changing the SV pool refilling time, and increases the Ca2+ sensitivity of glutamate release. It is a commonly accepted view that light stimulation of mammalian photoreceptors causes a graded change in membrane potential instead of developing a spike. The presynaptic Ca2+ channels serve as a crucial link for the coding of membrane potential variations into neurotransmitter release. Cav1.4 L-type Ca2+ channels are expressed in photoreceptor terminals, but the complete pool of Ca2+ channels in cone photoreceptors appears to be more diverse. Here, we discovered, employing whole-cell patch-clamp recording from cone photoreceptor terminals in both sexes of mice, that their Ca2+ currents are composed of low- (T-type Ca2+ channels) and high- (L-type Ca2+ channels) voltage-activated components. Furthermore, Ca2+ channels exerted self-generated spike behavior in dark membrane potentials, and spikes were generated in response to light/ dark transition. The application of fast and slow Ca2+ chelators revealed that T-type Ca2+ channels are located close to the release machinery. Furthermore, capacitance measurements indicated that they are involved in evoked vesicle release. Additionally, RT-PCR experiments showed the presence of Cav3.2 T-type Ca2+ channels in cone photoreceptors but not in rod photoreceptors. Altogether, we found several crucial functions of T-type Ca2+ channels, which increase the functional repertoire of cone photoreceptors. Namely, they extend cone photoreceptor light-responsive membrane potential range, amplify dark responses, generate spikes, increase intracellular Ca2+ levels, and boost synaptic transmission.
... The peak of I LVA and I HVA localized at approximately À40 mV and approximately À20 mV, respectively ( Fig. 1C3), and the presence of the two current types yielded a wide range of responsive V m . The first peak suggested the presence of T-type Ca 21 channels because the typical T-type I Ca reaches its maximal amplitude between À40 and À10 mV (Ertel et al., 1997). However, unlike T-type I Ca in other tissues, I LVA was not fully inactivated at À39 mV, a potential that is close to the physiological V m in darkness (À40 mV). ...
It is a commonly accepted view that light stimulation of mammalian photoreceptors causes a graded change in membrane potential instead of developing a spike. The presynaptic Ca2+ channels serve as a crucial link for the coding of membrane potential variations into neurotransmitter release. Cav1.4 L-type Ca2+ channels are expressed in photoreceptor terminals but the complete pool of Ca2+ channels in cone photoreceptors appears to be more diverse. Here, we discovered using whole-cell patch-clamp recording from cone photoreceptor terminals in both sexes of mice, that their Ca2+ currents are composed of low (T-type Ca2+ channels) and high (L-type Ca2+ channels) voltage-activated components. Furthermore, Ca2+ channels exerted self-generated spike behavior in dark membrane potentials, and spikes were generated in response to light/dark transition. The application of fast and slow Ca2+ chelators revealed that T-type Ca2+ channels are located close to the release machinery. Furthermore, capacitance measurements indicated that they are involved in evoked vesicle release. Additionally, RT-PCR experiments showed the presence of Cav3.2 T-type Ca2+ channels in cone photoreceptors but not in rod photoreceptors. Altogether, we found several crucial functions of T-type Ca2+ channels, which increase the functional repertoire of cone photoreceptors. Namely, they extend cone photoreceptor light-responsive membrane potential range, amplify dark responses, generate spikes, increase intracellular Ca2+ levels, and boost synaptic transmission.SIGNIFICANCE STATEMENTPhotoreceptors provide the first synapse for coding light information in daylight. The key elements in synaptic transmission are the voltage-sensitive Ca2+ channels. Here, we provide evidence that mouse cone photoreceptors express low-voltage-activated Cav3.2 T-type Ca2+ channels in addition to high-voltage-activated L-type Ca2+ channels. The presence of T-type Ca2+ channels in cone photoreceptors appears to extend their light-responsive membrane potential range, amplify dark response, generate spikes, increase intracellular Ca2+ levels, and boost synaptic transmission. By these functions, Cav3.2 T-type Ca2+ channels increase the functional repertoire of cone photoreceptors.
... On the other hand, CACNA1H (calcium voltage-gated channel subunit alpha1 H, also known as Cav3.2) encodes for Cav3.2 channel that is a member of the voltage-gated calcium channel family. This gene participates in the T-type Ca 2+ channels which contribute to signal transduction pathways regulating protein synthesis, development, proliferation and cell differentiation 34 that are mainly expressed during embryonic development 34 . Particularly, these channels are involved in the early stages of muscle differentiation in humans 35 37 and reduced litter size 38 . ...
The objective of the present study was to discover the genetic variants, functional candidate genes, biological processes and molecular functions underlying the negative genetic correlation observed between body weight (BW) and egg number (EN) traits in female broilers. To this end, first a bivariate genome-wide association and second stepwise conditional-joint analyses were performed using 2586 female broilers and 240 k autosomal SNPs. The aforementioned analyses resulted in a total number of 49 independent cross-phenotype (CP) significant SNPs with 35 independent markers showing antagonistic action i.e., positive effects on one trait and negative effects on the other trait. A number of 33 independent CP SNPs were located within 26 and 14 protein coding and long non-coding RNA genes, respectively. Furthermore, 26 independent markers were situated within 44 reported QTLs, most of them related to growth traits. Investigation of the functional role of protein coding genes via pathway and gene ontology analyses highlighted four candidates (CPEB3, ACVR1, MAST2 and CACNA1H) as most plausible pleiotropic genes for the traits under study. Three candidates (CPEB3, MAST2 and CACNA1H) were associated with antagonistic pleiotropy, while ACVR1 with synergistic pleiotropic action. Current results provide a novel insight into the biological mechanism of the genetic trade-off between growth and reproduction, in broilers.
... TTCCs are activated at more negative voltages (−60 mV) compared to LTCCs, which are activated at more depolarized voltages (−30 mV) (331,533). The current-voltage relationship for TTCCs shows a peak current at −15 mV whereas LTCCs show peak currents at +20 mV (108). LTCC and TTCC expression varies among different vascular beds and different-sized arteries within the same vascular bed. ...
The contractile state of resistance arteries and arterioles is a crucial determinant of blood pressure and blood flow. Physiological regulation of arterial contractility requires constant communication between endothelial and smooth muscle cells. Various Ca2+ signals and Ca2+ -sensitive targets ensure dynamic control of intercellular communications in the vascular wall. The functional effect of a Ca2+ signal on arterial contractility depends on the type of Ca2+ -sensitive target engaged by that signal. Recent studies using advanced imaging methods have identified the spatiotemporal signatures of individual Ca2+ signals that control arterial and arteriolar contractility. Broadly speaking, intracellular Ca2+ is increased by ion channels and transporters on the plasma membrane and endoplasmic reticular membrane. Physiological roles for many vascular Ca2+ signals have already been confirmed, while further investigation is needed for other Ca2+ signals. This article focuses on endothelial and smooth muscle Ca2+ signaling mechanisms in resistance arteries and arterioles. We discuss the Ca2+ entry pathways at the plasma membrane, Ca2+ release signals from the intracellular stores, the functional and physiological relevance of Ca2+ signals, and their regulatory mechanisms. Finally, we describe the contribution of abnormal endothelial and smooth muscle Ca2+ signals to the pathogenesis of vascular disorders. © 2021 American Physiological Society. Compr Physiol 11:1831-1869, 2021.
... 17,18,19 On the other hand, mibefradil at concentrations in the micromolar and nanomolar ranges, preferentially blocks T-type channels over HVA in vascular smooth muscle and in Purkinje cells. 20,21 Additional studies show that mibefradil also inhibits T-type currents in dissociated dorsal root ganglia (DRG) neurons, stabilizing the channel in the inactive state. 22 Mibefradil was the first compound marketed for selective T-type channel blockade. ...
T-type calcium channels regulate neuronal excitability and are important contributors of pain processing. CaV3.2 channels are the major isoform expressed in non-peptidergic and peptidergic nociceptive neurons and are emerging as promising targets for pain treatment. Numerous studies have shown that CaV3.2 expression and/or activity are significantly increased in spinal dorsal horn and in dorsal root ganglia neurons in different inflammatory and neuropathic pain models. Pharmacological campaigns to inhibit the functional expression of CaV3.2 for treatment of pain have focused on the development of direct channel blockers, but none have produced have lead candidates. Targeting the proteins that regulate the trafficking or transcription, and the ones that modify the channels via post-translational modifications are alternative means to regulate expression and function of CaV3.2 channels and hence to develop new drugs to control pain. Here we synthesize data supporting a role for CaV3.2 in numerous pain modalities and then discuss emerging opportunities for the indirect targeting of CaV3.2 channels.
... Overexpression of T-type calcium channels was recorded in many cancer cell lines compared with normal cells [40,41]. In addition, T-type calcium [42,43], and these channels may be involved in controlling the entry of extracellular calcium into the cells, which is important for cell-cycle progression [39,44]. Thus, T-type calcium channels were implicated in calcium-dependent biological processes associated with cellular growth, proliferation, and survival and may therefore be an effective anti-cancer target. ...
... Overexpression of T-type calcium channels was recorded in many cancer cell lines compared with normal cells [40,41]. In addition, T-type calcium channels prevail in various cells in the body [42,43], and these channels may be involved in controlling the entry of extracellular calcium into the cells, which is important for cell-cycle progression [39,44]. Thus, T-type calcium channels were implicated in calcium-dependent biological processes associated with cellular growth, proliferation, and survival and may therefore be an effective anti-cancer target. ...
Penfluridol has robust antipsychotic efficacy and is a first-generation diphenylbutylpiperidine. Its effects last for several days after a single oral dose and it can be administered once a week to provide better compliance and symptom control. Recently; strong antitumour effects for penfluridol were discovered in various cancer cell lines; such as breast; pancreatic; glioblastoma; and lung cancer cells via several distinct mechanisms. Therefore; penfluridol has drawn much attention as a potentially novel anti-tumour agent. In addition; the anti-cancer effects of penfluridol have been demonstrated in vivo: results showed slight changes in the volume and weight of organs at doses tested in animals. This paper outlines the potential for penfluridol to be developed as a next-generation anticancer drug.
... T-type Ca 2+ channels can be found in cells throughout the body, including neurons, myocardial cells, and muscle cells [1][2][3]. T-type Ca 2+ channels allow the influx of extracellular Ca 2+ at membrane potentials close to rest [4]. They may play an important role in several Ca 2+ -dependent cellular processes, including cell proliferation, survival, and differentiation. ...
... The Ca 2+ currents generated by T-type channels are transient as a result of voltage-dependent inactivation. Upon repolarization of the membrane, T-type Ca 2+ channels slowly close, which leads to a slowly deactivating tail current [4,24]. T-type Ca 2+ channels allow for the permeation of Ba 2+ into the cell [4,26]. ...
... Upon repolarization of the membrane, T-type Ca 2+ channels slowly close, which leads to a slowly deactivating tail current [4,24]. T-type Ca 2+ channels allow for the permeation of Ba 2+ into the cell [4,26]. T-type Ca 2+ channels can have activation and inactivation over similar voltage ranges. ...
Although voltage-activated Ca2+ channels are a common feature in excitable cells, their expression in cancer tissue is less understood. T-type Ca2+ channels are particularly overexpressed in various cancers. Because of their activation profile at membrane potentials close to rest and the generation of a window current, T-type Ca2+ channels may regulate a variety of Ca2+-dependent cellular processes, including cell proliferation, survival, and differentiation. The expression of T-type Ca2+ channels is of special interest as a target for therapeutic interventions.
... They produce electrical signals that are crucial for diverse physiological functions, for example, generation of electrical activity in nerves and muscles, cardiac excitability, hormone secretion, intracellular signaling, cell growth, cell proliferation, and cell volume regulation (Alberts et al., 2002;Lang et al., 2005;Nadal et al., 2004). Accumulating evidence suggests Introduction susceptibility, altered cardiac excitability, disorders of muscle cells, and neurodegenerative diseases (Ertel et al., 1997;Hool & Corry, 2007;Huguenard, 1996;Kolbe et al., 2010). ...
... Thus, the antiproliferative effects of mibefradil may derive, at least partly, from its specific blockade of T-type Ca 2+ channels, although it also has effects on the L-type channels. A role for T-type Ca 2+ channels in proliferation and growth has indeed been suggested [19] as well as in the prevention of excessive adhesion of leukocytes [1] and the reduction in the transmigration of leukocytes in the tissue [1,20]. ...
