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G-protein interaction sites. An outline of primary structure of the α 1 subunit of N-type calcium channel. Barrels (S1-S6) represent transmembrane segments in domains I-IV. Open boxes indicate regions in the α 1 subunit sequence interacting with the Gprotein Gβγ subunit.
Source publication
N-type or CaV2.2 high-voltage activated calcium channels are distinguished by exclusively neuronal tissue distribution, sensitivity to ω-conotoxins, prominent inhibition by G-proteins, and a unique role in nociception. Most investigated modulatory pathway regulating the CaV2.2 channels is G-protein-coupled receptor-activated pathway leading to curr...
Context in source publication
Context 1
... gating state is characterized by a direct binding of the Gβγ dimer to the Ca V 2.2 α 1 subunit. Multiple interaction sites were identified in the Ca V 2.2 α 1 sequence ( Figure 2): the aminoterminal part ( Page et al. 1998;Stephens et al. 1998;Agler et al. 2005;Page et al. 2010), the intracellular loop connecting domains I and II (De Waard et al. 1997;Herlitze et al. 1997;Page et al. 1997;Simen and Miller 1998;Van Petegem et al. 2004;Tedford et al. 2010), and the carboxyterminal part ( Zhang et al. 1996;Qin et al. 1997). ...
Similar publications
Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal tra...
Citations
... N-type calcium channels are characterized by their exclusively neuronal tissue distribution, prominent inhibition by G-proteins, and their participation in nociception [12]. They are sensitive to ω-conotoxins, small neurotoxic peptides isolated from the venom of sea snails of the genus Conus [13], some of which have been used in functional assays and for pharmacological purposes [14]. ...
... The auxiliary subunits α2δ1, α2δ2, and β4 may have different effects in the α1B subunit and coffered different properties to the N-Type channels [12]. ...
N-type voltage-gated calcium channel controls the release of neurotransmitters from neurons. The association of other voltage-gated calcium channels with epilepsy is well-known. The association of N-type voltage-gated calcium channels and pain has also been established. However, the relationship between this type of calcium channel and epilepsy has not been specifically reviewed. Therefore, the present review systematically summarizes existing publications regarding the genetic associations between N-type voltage-dependent calcium channel and epilepsy.
... The N-type Ca 2+ channel voltage-gated calcium channel (Ca V )2.2, which induces peripheral neuron neurotransmission [51], is degraded via the UPS to maintain the precise modulation of its expression [52,53]. For example, the overexpression of Parkin, which is an E3 ligase, decreases the current of Ca V 2.2 through proteasome-induced degradation [52], and proteasome inhibition through MG-132 increases the current of Ca V 2.2 [53]. ...
The ubiquitin–proteasome system (UPS) is the main proteolytic pathway by which damaged target proteins are degraded after ubiquitination and the recruit of ubiquitinated proteins, thus regulating diverse physiological functions and the maintenance in various tissues and cells. Ca2+ signaling is raised by oxidative or ER stress. Although the basic function of the UPS has been extensively elucidated and has been continued to define its mechanism, the precise relationship between the UPS and Ca2+ signaling remains unclear. In the present review, we describe the relationship between the UPS and Ca2+ signaling, including Ca2+-associated proteins, to understand the end point of oxidative stress. The UPS modulates Ca2+ signaling via the degradation of Ca2+-related proteins, including Ca2+ channels and transporters. Conversely, the modulation of UPS is driven by increases in the intracellular Ca2+ concentration. The multifaceted relationship between the UPS and Ca2+ plays critical roles in different tissue systems. Thus, we highlight the potential crosstalk between the UPS and Ca2+ signaling by providing an overview of the UPS in different organ systems and illuminating the relationship between the UPS and autophagy.
... Unlike the low-threshold calcium channels, the high-threshold voltage-gated calcium channels are heteromultimeric proteins [67]. Ca V 2.2 channels consist of principal α1 and auxiliary β, and α 2 δ subunits encoded by multiple genes [55]. ...
... The α 2 δ1 was shown to be necessary for the trafficking of the channel complex into the plasma membrane in DRG neurons [100]. Modulatory effects of all auxiliary subunits are predominantly of gain-of-function type [55]. ...
Noxious stimuli like cold, heat, pH change, tissue damage, and inflammation depolarize a membrane of peripheral endings of specialized nociceptive neurons which eventually results in the generation of an action potential. The electrical signal is carried along a long axon of nociceptive neurons from peripheral organs to soma located in dorsal root ganglions and further to the dorsal horn of the spinal cord where it is transmitted through a chemical synapse and is carried through the spinal thalamic tract into the brain. Two subtypes of voltage-activated calcium play a major role in signal transmission: a low voltage-activated CaV3.2 channel and a high voltage-activated CaV2.2 channel. The CaV3.2 channel contributes mainly to the signal conductance along nociceptive neurons while the principal role of the CaV2.2 channel is in the synaptic transmission at the dorsal horn. Both channels contribute to the signal initiation at peripheral nerve endings. This review summarizes current knowledge about the expression and distribution of these channels in a nociceptive pathway, the regulation of their expression and gating during pain pathology, and their suitability as targets for pharmacological therapy.
... [4,5] NP activates N-methyl-D-aspartate (NMDA) receptors especially NR2B, [6][7][8] the capsaicin receptor transient receptor potential channels especially TRPV1, also known as vanilloid receptor, [9][10][11] N-type or high-voltage activated calcium channels especially CaV2.2 is associated with inflammation. [12][13][14] Recent studies have suggested that NR2B, TRPV1 and voltage-gated calcium (CaV2.2) channels are the emerging targets for treating neuropathic pain. [10,12,13] Macrophages, chemokines, cytokines (TNF-α, IL-6, IL-1β) are the key players of inflammation in peripheral nerve injuries. ...
... [12][13][14] Recent studies have suggested that NR2B, TRPV1 and voltage-gated calcium (CaV2.2) channels are the emerging targets for treating neuropathic pain. [10,12,13] Macrophages, chemokines, cytokines (TNF-α, IL-6, IL-1β) are the key players of inflammation in peripheral nerve injuries. [15] Sommer et al. [16] also reported that anti-inflammatory agents targeting these key players would provide a better therapeutic strategy in neuropathic pain. ...
Objectives:
Neuropathic pain (NP) is a chronic inflammation of the sciatic nerve, associated with complex pathophysiological events like neuronal ectopic discharge with changes in neurotransmitters, growth factors, receptors/ion channels including N-methyl-d-aspartate receptors, Transient receptor cation channels, Voltage-gated calcium channels. All these events eventually lead to inflammation and apoptosis of the sciatic nerve in NP. Icariin (ICA), a natural flavonoid is well known for its anti-inflammatory potential. Hence, the present study is designed to evaluate its anti-inflammatory potential against neuropathic pain using in silico and in vivo studies.
Methods:
In silico studies were conducted using targets of N-methyl-D-aspartate receptor subtype-2B (NR2B), The capsaicin receptor transient receptor cation channel subfamily-V member-1 (TRPV1), N-type voltage-gated calcium (CaV2.2) channels. In in vivo studies, after partial sciatic nerve ligation surgery to animals, received their respective treatment for 21 days, further TNF-α, IL-6, Bax (proapoptotic) and Bcl-2 (antiapoptotic) expressions were estimated.
Key findings:
ICA decreased the expressions of TNF-α, IL-6, Bax and increased expression of Bcl-2. In silico studies revealed a good energy binding score towards NR2B, TRPV1 receptors and CaV2.2 ion Channel.
Conclusions:
ICA could be a promising agent in alleviating neuropathic pain by inhibiting NR2B, TRPV1 receptors and Cav2.2 channels, which induces anti-apoptotic potential and inhibits inflammation.
... Modulation of the N-type Ca 2+ channels by G-proteins is most extensively studied and was recently reviewed by several authors [20][21][22][23]. To describe the alteration of channel gating upon interaction with G-proteins, a model of "willing" and "reluctant" gating states was introduced [24,25]. ...
... Schematic depiction of the role of presynaptic Ca V 2.2 in signal transmission in a nociceptive synapse. Modified from[22] with permission. ...
Voltage-gated Ca²⁺ channels are typically integrated in a complex network of protein-protein-interactions, also referred to as Ca²⁺ channel nanodomains. Amongst the neuronal CaV2 channel family, CaV2.2 is of particular importance due to its general role for signal transmission from the periphery to the central nervous system, but also due to its significance for pain perception. Thus, CaV2.2 is an ideal target candidate to search for pharmacological inhibitors but also for novel modulatory interactors. In this review we summarize the last years findings of our intense screenings and characterization of the six CaV2.2 interaction partners, tetraspanin-13 (TSPAN-13), reticulon 1 (RTN1), member 1 of solute carrier family 38 (SLC38), prostaglandin D2 synthase (PTGDS), transmembrane protein 223 (TMEM223), and transmembrane BAX inhibitor motif 3 (Grina/TMBIM3) containing protein. Each protein shows a unique way of channel modulation as shown by extensive electrophysiological studies. Amongst the newly identified interactors, Grina/TMBIM3 is most striking due to its modulatory effect which is rather comparable to G-protein regulation.
... Modulation of the N-type Ca 2+ channels by G-proteins is most extensively studied and was recently reviewed by several authors [20][21][22][23]. To describe the alteration of channel gating upon interaction with G-proteins, a model of "willing" and "reluctant" gating states was introduced [24,25]. ...
... Schematic depiction of the role of presynaptic Ca V 2.2 in signal transmission in a nociceptive synapse. Modified from[22] with permission. ...
Voltage-gated Ca2+ channels are typically integrated in a complex network of protein-protein-interactions, also referred to as Ca2+ channel nanodomains. Amongst the neuronal CaV2 channel family, CaV2.2 is of particular importance due to its general role for signal transmission from the periphery to the central nervous system, but also due to its significance for pain perception. Thus, CaV2.2 is an ideal target candidate to search for pharmacological inhibitors but also for novel modulatory interactors. In this review we summarize the last years findings of our intense screenings and characterization of the six CaV2.2 interaction partners, tetraspanin-13 (TSPAN-13), reticulon 1 (RTN1), member 1 of solute carrier family 38 (SLC38), prostaglandin D2 synthase (PTGDS), transmembrane protein 223 (TMEM223), and transmembrane BAX inhibitor motif 3 (Grina/TMBIM3) containing protein. Each protein shows a unique way of channel modulation as shown by extensive electrophysiological studies. Amongst the newly identified interactors, Grina/TMBIM3 is most striking due to its modulatory effect which is rather comparable to G-protein regulation.
... Ca v 2.2 channel subtypes are known as N-type because they are exclusively neuronal and express a Ca ++ current component that is different from L-type (Ca v 1.1-Ca v 1.4) or T-type (Ca v 3.1−Ca v 3.3) components [176,179]. Thus, these channel subtypes are involved in nociception more than in any other physiologic process [180]. Interestingly, from of MVIIA, a ω-conotoxin purified from Conus magus venom, was developed Prialt TM as drug for the treatment of neuropathic pain [181]. ...
Cone snails are marine gastropod mollusks with one of the most powerful venoms in nature. The toxins, named conotoxins, must act quickly on the cone snails´ prey due to the fact that snails are extremely slow, reducing their hunting capability. Therefore, the characteristics of conotoxins have become the object of investigation, and as a result medicines have been developed or are in the trialing process. Conotoxins interact with transmembrane proteins, showing specificity and potency. They target ion channels and ionotropic receptors with greater regularity, and when interaction occurs, there is immediate physiological decompensation. In this review we aimed to evaluate the structural features of conotoxins and the relationship with their target types.
Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described by the patient in terms of such damage”. The origin of every pain syndrome is inflammation. A group of voltage-gated channels that are permeable to calcium ions enhances sensory transduction witnessed during inflammation. Hence, understanding calcium signaling is an essential step towards recognizing neural network activity associated with pain management. In this review, we attempted to understand the impact of calcium-permeable ion channels in the recognition, processing, transduction and modulation of pain signals. Results obtained revealed that calcium being one of the most ubiquitous secondary messengers play a significant role in modulating numerous biological processes, including inflammation and pain. Though almost all subtypes of calcium channels are highly expressed in the central nervous system (CNS), the “N-type calcium ion-channels” play an important function at the time of neurotransmitter release from the afferent terminals within the spinal dorsal. Hence, they serve as a key therapeutic target during the treatment of analgesics. Migraine is also reported to involve neurogenic inflammation. “P/Q-type calcium channels” is suggested to have important role in migraine. The inhibition of these channels through various analgesics serves as a treatment against inflammatory and neuropathic pain. However, few of these inhibitors have numerous side effects, including cancer. Hence, these inhibitors may be consumed under the supervision of medical practitioners. In this review, we revealed the understanding and regulation of ion channels in inflammation causing pain and its treatment.
Calcium (Ca 2+) is an important second messenger in charge of many critical processes in the central nervous system (CNS), including membrane excitability, neurotransmission, learning, memory, cell proliferation, and apoptosis. In this way, the voltage-gated calcium channels (VGCCs) act as a key supply for Ca2+ entry into the cytoplasm and organelles. Importantly, the dysregulation of these channels has been reported in many neurological diseases of young-onset, with associated genetic factors, such as migraine, multiple sclerosis, and Huntington’s disease. Notably, the literature has pointed to the role of N-type Ca2+ channels (NTCCs) in controlling a variety of processes, including pain, inflammation, and excitotoxicity. Moreover, several Ca2+ channel blockers that are used for therapeutic purposes have been shown to act on the N-type channels. Therefore, this review provides an overview of the NTCCs in neurological disorders focusing mainly on Huntington’s disease, multiple sclerosis, and migraine. It will discuss possible strategies to generate novel therapeutic strategies.
This chapter of the book is directed to PhD students, post-docs and young researchers who are attracted by the unique properties of voltage-gated calcium channels. The chapter aims to provide an overview of the most important discoveries that helped elucidate the structure and function of calcium channels in excitable cells. While systematically reviewing the numerous works in the field, I chose to write a personal story derived from my own experience on Ca2+ channels, as it developed in the lab and through the discussions with many colleagues working on ion channels. This occurred in a period in which Ca2+ channels reached maximal attention among scientists and brought the many astonishing achievements described in this book. Given the broad interdisciplinarity of Ca2+ channel discoveries, the present history may probably appear incomplete, but certainly, the other chapters of the book will cover all possible gaps on the matter.
