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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
The mammalian transmembrane ACs have a similar topology, which comprises a variable N-terminus and two repeats of a membrane-spanning domain (C1a and C2a), followed by a cytoplasmic domain. The C1a and C2a subdomains are homologous and form the active site of the enzyme. The two cytoplasmic domains (C1 and C2) form an intramolecular “dimer” at their interface, thereby creating a site that is primed for bidirectional regulation. In the absence of activators, the relative affinity between the C1 and C2 domains is weak, while forskolin or Gs each increases their affinity by 10-fold. Forskolin binds at the interface, while Gs binds at a cleft on the opposite side of the catalytic site. Synergistic activation by both regulators results in a 100-fold increase in affinity in the active site.
Cellular and Molecular Imaging of the Diabetic Pancreas
Published in Michel M. J. Modo, Jeff W. M. Bulte, Molecular and Cellular MR Imaging, 2007
The relevance of our findings to magnetic resonance imaging becomes apparent when considering the fact that annexin V labeled with superparamagnetic iron oxides (annexin V-CLIO) has shown promise as an apoptosis imaging agent in tumor cells.115 In that study, tumor cells treated with the pro-apoptotic agent camptothecin were incubated with annexin V-CLIO, resulting in a significant signal decrease in phantom MRI experiments even at very low concentrations of magnetic substrate. More recently, annexin V-CLIO-Cy5.5 has been applied in vivo to a model of cardiomyocyte apoptosis.116 Intravenous injection of this nanoparticle into mice subjected to transient coronary artery occlusion resulted in reduction in T2* relaxivity values. In another study, superparamagnetic iron oxides were conjugated to the C2 domain of synaptotagmin I, which binds to anionic phospholipids in cell membranes.117 This conjugate successfully detected cell death in vitro in isolated apoptotic tumor cells, and in vivo in a tumor treated with chemotherapeutic drugs. Having in mind the demonstrated applicability of fluorescently labeled annexin V to diabetes imaging and the encouraging results using iron oxide conjugates for the molecular imaging of apoptosis by MRI, it appears that the development of similar strategies in the context of diabetes-associated cell death represents a promising avenue to pursue in the future, particularly since levels of apoptosis are comparable in these models.105,116 In fact, the feasibility of this approach is underscored by the earlier observation that an increase of as much as 30% in T2* relaxation (1/T2*) can be effected at levels of apoptosis around 3%.116
Exocytosis of Nonclassical Neurotransmitters
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Xiao Su, Vincent R. Mirabella, Kenneth G. Paradiso, Zhiping P. Pang
It is not known whether LDCV exocytosis relies on specific Ca2+ sensor proteins or what the molecular identity of Ca2+-binding proteins triggering neuropeptide release from neurons is. Ca2+-binding proteins in the mouse genome can be classified into three categories based on analysis of their protein domain structures using protein the SMART database: C2 domain containing proteins, EF-hand proteins, annexins, and others. C2 domain proteins include all 17 members of Syts, Doc2s, MCTP1–2, Ferlins, Esyt1–3, Copine1–9, SytL1–5, Rab11fip1–5, CC2d1–2, PLCs, PKCs, Munc13s; E-F hand proteins include CaM1–3, NeCab1–3, NCS1, Efcab1–5, Calbinidin1–2, Casbp22; Annexin 1–11; Others include Plscls1–4; rolling balckout1–2; and syntaxin 1. Conclusively identifying the Ca2+ sensor(s) and release mode of neuropeptides/DCV fusion will represent a significant advance in our fundamental knowledge of brain function. As mentioned, Syts form a large protein family composed of 17 members. Eight Syts (Syt 1–3, 5–7, 9, and 10) have unambiguous Ca2+-binding sites in their C2 domains. Therefore, it will be a significant effort to systematically address the possible involvement of Syts in LDCV release. It is well established that Syt 1 and 2 are the primary Ca2+ sensors for fast, synchronous SV release, as described in the introductory material (Pang and Südhof, 2010). It has been shown that Syt 1 and 7 are also involved in insulin release (Gustavsson et al., 2008) and Syt 10 is involved in IGF release (Cao et al., 2011). Thus, there is a strong basis for the hypothesis that some of Syts may be involved in neuropeptide release. Nevertheless, an unambiguous role for Syts in mediating Ca2+-dependent neuropeptide release in the brain is not clearly established.
Role of RAGE and its ligand HMGB1 in the development of COPD
Published in Postgraduate Medicine, 2022
Lin Chen, Xuejiao Sun, Xiaoning Zhong
The full-length/membrane RAGE (mRAGE) consists of: an extracellular structure with one V and two C domains, a short transmembrane domain, and a highly charged cytoplasmic tail that is critical for intracellular signal transduction [11,12]. The V and C1 domains are positively charged and are the binding regions of most of the distributors. Meanwhile, the C2 domain is negatively charged and binds to a small number of ligands. RAGE can bind ligands only after it is preassembled into a polymer consisting of four or more molecules on the cell surface [12,13]. Only by binding to adaptor proteins (e.g. DIAPH1, TIRAP, MyD88, DOCK7) [14], the intracellular domain of the cytoplasmic tail can activate the downstream signaling pathway [15,16], while the truncation of this specific domain can block downstream responses of RAGE and reduce its effects [14].
Novel alterations of CC2D1A as a candidate gene in a Turkish sample of patients with autism spectrum disorder
Published in International Journal of Neuroscience, 2022
Elif Funda Sener, Muge Gulcihan Onal, Fatma Dal, Ufuk Nalbantoglu, Yusuf Ozkul, Halit Canatan, Didem Behice Oztop
The coiled-coil and C2 domain-containing protein 1 A (CC2D1A) gene was identified as a repressor of serotonin receptor 1 A (HTR1A) expression [13]. CC2D1A gene contains Drosophila melanogaster 14 (DM14), protein kinase C conserved region 2 (C2)/calcium-dependent lipid-binding calcium/phospholipid binding domain and a predicted helix-loop-helix DNA-binding domain [13–15]. CC2D1A gene (24,640 bp) contains 29 exons and is located on 19p13.12 [16]. CC2D1A was originally identified as an activator of the NF-κB promoter [17]. Loss-of-function mutations in CC2D1A gene have been associated with severe autosomal recessive nonsyndromic mental retardation (NSMR) in human patients, but the biochemical function of this protein is not fully understood [15,18]. The truncation mutation in NSMR patients causes deletion of one of the four DM14 domains, and the C2 domains are very important for the gene function [15]. In our previous study, we investigated the expressions of CC2D1A gene in the autism patients. As a result of our study, the expression of CC2D1A gene may be used as a candidate gene for ASD cases with ID [19].
Identification, characterization, and comparison of n-alkanols and anesthetics binding to the C1b subdomain of protein kinase cα: similar function with different binding sites
Published in Journal of Receptors and Signal Transduction, 2020
Fang Lian, Zhong Wang, Zhidong Zhou, Guohai Xu
Protein kinase C (PKC) family members regulate numerous cellular responses including gene expression, protein secretion, cell proliferation, and the inflammatory response. The PKC enzymes can be divided into 3 broad groups in terms of the differences in their regulatory regions [1]. Conventional PKCs (including PKCα, PKCβ, and PKCγ isoforms) contain two functional C1 and C2 regulatory domains, of which the activation requires binding of endogenous phospholipid (PE) and diacylglycerol (DG) to the C1 domain as well as calcium binding to the C2 domain. Novel PKCs (including PKCδ, PKCε, PKCη, and PKCθ isoforms) also require DG binding for activation but contain a novel C2 domain that does not act as a calcium sensor. Atypical PKCs (including PKCζ and PKCι/λ isoforms) contain a nonfunctional C1 domain and lack the C2 domain, requiring no second messenger for their activation [2].