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1.
Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated pore loop channels. HCN channels are unique among
vertebrate voltage-gated ion channels, in that they have a reverse voltage-dependence that leads to activation upon hyperpolarization.
In addition, voltage-dependent opening of these channels is directly regulated by the binding of cAMP. HCN channels are encoded
by four genes (HCN1–4) and are widely expressed throughout the heart and the central nervous system. The current flowing through
HCN channels, designated Ih or If, plays a key role in the control of cardiac and neuronal rhythmicity (“pacemaker current”). In addition, Ih contributes to several other neuronal processes, including determination of resting membrane potential, dendritic integration
and synaptic transmission. In this review we give an overview on structure, function and regulation of HCN channels. Particular
emphasis will be laid on the complex roles of these channels for neuronal function and cardiac rhythmicity.
Received 22 August 2008; received after revision 22 September 2008; accepted 24 September 2008 相似文献
2.
Summary Studies have implicated Ca++ in the actions of ethanol at many biochemical levels. Calcium as a major intracellular messenger in the central nervous system is involved in many processes, including protein phosphorylation enzyme activation and secretion of hormones and neurotransmitters. The control of intracellular calcium, therefore, represents a major step by which neuronal cells regulate their activities. The present review focuses on three primary areas which influence intracellular calcium levels; voltage-dependent Ca++ channels, receptor-mediated inositol phospholipid hydrolysis, and Ca++/Mg++-ATPase, the high affinity membrane Ca++ pump.Current research suggests that a subtype of the voltage-dependent Ca++ channel, the dihydropyridine-sensitive Ca++ channel, is uniquely sensitive to acute and chronic ethanol treatment. Acute exposure inhibits, while chronic ethanol exposure increases45Ca++-influx and [3H]dihydropyridine receptor binding sites. In addition, acute and chronic exposure to ethanol inhibits, then increases Ca++/Mg++-ATPase activity in neuronal membranes. Changes in Ca++ channel and Ca++/Mg++-ATPase activity following chronic ethanol may occur as an adaptation process to increase Ca++ availability for intracellular processes. Since receptor-dependent inositol phospholipid hydrolysis is enhanced after chronic ethanol treatment, subsequent activation of protein kinase-C may also be involved in the adaptation process and may indicate increased coupling for receptor-dependent changes in Ca++/Mg++-ATPase activity.The increased sensitivity of three Ca++-dependent processes suggest that adaptation to chronic ethanol exposure may involve coupling of one or more of these processes to receptor-mediated events. 相似文献
3.
Sayuri Suzuki Annette Lis Carsten Schmitz Reinhold Penner Andrea Fleig 《Cellular and molecular life sciences : CMLS》2018,75(16):3069-3078
The melastatin-related transient receptor potential member 7 (TRPM7) is a unique fusion protein with both ion channel function and enzymatic α-kinase activity. TRPM7 is essential for cellular systemic magnesium homeostasis and early embryogenesis; it promotes calcium transport during global brain ischemia and emerges as a key player in cancer growth. TRPM7 channels are negatively regulated through G-protein-coupled receptor-stimulation, either by reducing cellular cyclic adenosine monophosphate (cAMP) or depleting phosphatidylinositol bisphosphate (PIP2) levels in the plasma membrane. We here identify that heterologous overexpression of human TRPM7-K1648R mutant will lead to disruption of protease or purinergic receptor-induced calcium release. The disruption occurs at the level of Gq, which requires intact TRPM7 kinase phosphorylation activity for orderly downstream signal transduction to activate phospholipase (PLC)β and cause calcium release. We propose that this mechanism may support limiting GPCR-mediated calcium signaling in times of insufficient cellular ATP supply. 相似文献
4.
D. Evéquoz E. Grouzmann A. G. Beck-Sickinger H. -R. Brunner B. Waeber 《Cellular and molecular life sciences : CMLS》1994,50(10):936-938
Neuropeptide Y (NPY) increases blood pressure either directly or indirectly by potentiating the effect of various vasoconstrictors. Only one (the Y1-receptor) of two subtypes of receptors (Y1 and Y2) is thought to mediate the vascular smooth muscle contraction. To test this hypothesis we challenged isolated rat mesenteric arteries that had a functional endothelium with (1–36) NPY and with specific Y1-receptor ([Leu31, Pro34] NPY) and Y2-receptor ([Ahx5–24, -Glu2--Lys30] NPY) agonists. The Y1-receptor agonist elicited a contractile response similar to that of NPY, whereas the Y2-receptor agonist had no effect on wall tension. We also found that the presence of a functional endothelium has no influence on the contractile response to NPY. From these data we conclude that the direct contractile effect of NPY in the mesenteric artery is mediated by stimulation of Y1-receptors and is not endothelium-dependent. 相似文献
5.
Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action 总被引:3,自引:0,他引:3
Montecucco C Gutiérrez JM Lomonte B 《Cellular and molecular life sciences : CMLS》2008,65(18):2897-2912
A large variety of snake toxins evolved from PLA2 digestive enzymes through a process of ‘accelerated evolution’. These toxins have different tissue targets, membrane receptors
and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA2s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which
is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation
which promotes a large increase of the cytosolic Ca2+ concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular
junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms
of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.
Received 05 March 2008; received after revision 08 April 2008; accepted 29 April 2008 相似文献
6.
P. J. Lardone A. Carrillo-Vico P. Molinero A. Rubio J. M. Guerrero 《Cellular and molecular life sciences : CMLS》2009,66(3):516-525
Human lymphocyte melatonin, through membrane and nuclear receptors binding, acts as an activator in IL-2 production. Antagonism
of membrane melatonin receptors using luzindole exacerbates the drop of the IL-2 production induced by PGE2 in peripheral blood mononuclear and Jurkat cells. This paper studies the melatonin membrane and nuclear receptors interplay
in PGE2-diminished IL-2 production. The decrease in IL-2 production after PGE2 and/or luzindole administration correlated with downregulation in the nuclear receptor RORα. We also highlighted a role of
cAMP in the pathway, because forskolin mimicked the effects of luzindole and/or PGE2 in the RORα expression. Finally, a significant RORα downregulation was observed in T cells permanently transfected with inducible
MT1 antisense. In conclusion, we show a novel connection between melatonin membrane receptor signalling and RORα expression,
opening a new way to understand melatonin regulation in lymphocyte physiology.
Received 23 September 2008; received after revision 19 November 2008; accepted 21 November 2008 相似文献
7.
Poulsen LR López-Marqués RL Palmgren MG 《Cellular and molecular life sciences : CMLS》2008,65(20):3119-3125
Our understanding of flippase-mediated lipid translocation and membrane vesiculation, and the involvement of P-type ATPases
in these processes is just beginning to emerge. The results obtained so far demonstrate significant complexity within this
field and point to major tasks for future research. Most importantly, biochemical characterization of P4-ATPases is required in order to clarify whether these transporters indeed are capable of catalyzing transmembrane phospholipid
flipping. The β-subunit of P4-ATPases shows unexpected similarities between the β- and γ-subunits of the Na+/K+-ATPase. It is likely that these proteins provide a similar solution to similar problems, and might have adopted similar structures
to accomplish these tasks. No P4-ATPases have been identified in the endoplasmic reticulum and it remains an intriguing possibility that, in this compartment,
P5A-ATPases are functional homologues of P4-ATPases.
Received 19 June 2008; received after revision 31 July 2008; accepted 15 August 2008 相似文献
8.
Large conductance, Ca2+-activated potassium (BK) channels are widely expressed throughout the animal kingdom and play important roles in many physiological
processes, such as muscle contraction, neural transmission and hearing. These physiological roles derive from the ability
of BK channels to be synergistically activated by membrane voltage, intracellular Ca2+ and other ligands. Similar to voltage-gated K+ channels, BK channels possess a pore-gate domain (S5–S6 transmembrane segments) and a voltage-sensor domain (S1–S4). In addition,
BK channels contain a large cytoplasmic C-terminal domain that serves as the primary ligand sensor. The voltage sensor and
the ligand sensor allosterically control K+ flux through the pore-gate domain in response to various stimuli, thereby linking cellular metabolism and membrane excitability.
This review summarizes the current understanding of these structural domains and their mutual interactions in voltage-, Ca2+ - and Mg2+ -dependent activation of the channel.
Received 25 September 2008; received after revision 23 October 2008; accepted 24 October 2008 相似文献
9.
Nabeshima Y 《Cellular and molecular life sciences : CMLS》2008,65(20):3218-3230
The traditional view of calcium homeostasis is that it is maintained by two essential reactions. First, changes in extracellular
Ca2+ are sensed in several distinct cell types, stimulating the secretion of parathyroid hormone (PTH), 1,25(OH)2 D and calcitonin in response to the body’s requirement. Second, these calcitropic hormones then act on the calcium-translocating
cells of the kidney, bone, and intestine to restore calcium balance. Recent progress indicates that α-Klotho and fibroblast
growth factor (FGF) 23 are key players that integrate the multi-step regulatory system of calcium homeostasis that rapidly
adjusts the extracellular calcium concentration and continuously maintains its concentration within a narrow physiological
range. α-Klotho and FGF23 are also found to be major players in the regulatory system of phosphate homeostasis. Here, the
demonstration of the molecular functions of α-Klotho and FGF23 has recently given new insight into the field of calcium and
phosphate homeostasis.
Received 3 April 2008; received after revision 23 May 2008; accepted 5 June 2008 相似文献
10.
Wang SH Shih YL Ko WC Wei YH Shih CM 《Cellular and molecular life sciences : CMLS》2008,65(22):3640-3652
The cytotoxicity of cadmium (Cd) induced autophagy and apoptosis in MES-13 cells was determined by flow cytometry. Autophagy
was also assessed by formation of autophagosomes and processing of LC3. Pharmacological inhibition of autophagy resulted in
increased of cell viability, suggesting autophagy plays a role in cell death in Cd-treated mesangial cells. Cd also induced
a rapid elevation in cytosolic calcium ([Ca2+]i ), and modulation of [Ca2+]i via treatment with IP
3R inhibitor or knockdown of calcineurin resulted in a change in the proportion of cell death, suggesting that the release
of calcium from the ER plays a crucial role in Cd-induced cell death. Inhibition of Cd-induced ERK activation by PD 98059
suppressed Cd-induced autophagy, and BAPTA-AM eliminated activation of ERK. BAPTA-AM also inhibited Cd-induced mitochondrial
depolarization and activation of caspases. These findings demonstrated that Cd induces both autophagy and apoptosis through
elevation of [Ca2+]i, followed by Ca2+-ERK and Ca2+-mitochondria-caspase signaling pathways.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 05 July 2008; received after revision 25 August 2008; accepted 17 September 2008 相似文献
11.
12.
D. Parolini M. Meregalli M. Belicchi P. Razini R. Lopa B. Del Carlo A. Farini S. Maciotta N. Bresolin L. Porretti M. Pellegrino Y. Torrente 《Cellular and molecular life sciences : CMLS》2009,66(4):697-710
Among the heterogeneous population of circulating hematopoietic and endothelial progenitors, we identified a subpopulation
of CD133+ cells displaying myogenic properties. Unexpectedly, we observed the expression of the B-cell marker CD20 in blood-derived
CD133+ stem cells. The CD20 antigen plays a role in the modulation of intracellular calcium homeostasis through signaling pathways
activation. Several observations suggest that an increase in intracellular calcium concentration ([Ca2+]i) could be involved in the etiology of the Duchenne muscular dystrophy (DMD). Here, we show that a CD20-related signaling
pathway able to induce an increase in [Ca2+]i is differently activated after brain derived neurotrophic factor (BDNF) stimulation of normal and dystrophic blood-derived
CD133+ stem cells, supporting the assumption of a “CD20-related calcium impairment-affecting dystrophic cells. Presented findings
represent the starting point toward the expansion of knowledge on pathways involved in the pathology of DMD and in the behavior
of dystrophic blood-derived CD133+ stem cells.
Received 15 October 2008; received after revision 27 November 2008; accepted 05 December 2008 相似文献
13.
Inoue K 《Cellular and molecular life sciences : CMLS》2008,65(19):3074-3080
Accumulating findings indicate that nucleotides play an important role in microglia through P2 purinoceptors. P2 purinoceptors
are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (7 types; P2X1 – P2X7) contain intrinsic pores that open by binding with ATP. P2Y receptors (8 types; P2Y1, 2, 4, 6, 11, 12, 13 and 14) are activated by nucleotides and couple to intracellular second-messenger systems through heteromeric G-proteins. Nucleotides
are released or leaked from non-excitable cells as well as neurons in physiological and pathophysiological conditions. Microglia
express many types of P2 purinoceptors and are known as resident macrophages in the CNS. ATP and other nucleotides work as
‘warning molecules’ especially through activating microglia in pathophysiological conditions. Microglia play a key role in
neuropathic pain, chemotaxis and phagocytosis through nucleotide-evoked activation of P2X4, P2Y12 and P2Y6 receptors, respectively. These findings indicate that extracellular nucleotides are important players in the central stage
of microglial function.
Received 19 April 2008; received after revision 20 May 2008; accepted 23 May 2008 相似文献
14.
M. Ochsner 《Cellular and molecular life sciences : CMLS》1996,52(9):856-864
The dose-dependent effect of CGP 45715A on the LTD4-induced Ca2+ response of glomerular mesangial cells has been studied. Our results demonstrate that the LTD4-dependent increase in the cytosolic Ca2+ concentration primarily involves an InsP3-mediated release of Ca2+ from intracellular storage sites and to a minor extent an enhanced influx of Ca2+ through receptor-operated Ca2+ channels located in the plasma membrane. The action of CGP 45715A on the Ca2+ response is an inhibitory one and is convincingly explained by a displacement of LTD4 from its receptor site(s). The contractile effect of LTD4 on pulmonary smooth muscle is proposed to be mainly caused by a receptor-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate. 相似文献
15.
Spermatozoa generated in the testis are immature and incompetent for fertilization. During their journey toward the egg, the
sperm acquire fertility and achieving fertilization. These sperm modifications to ensure fertilization are induced by many
female or male extra-sperm factors: for example, sperm motility-activating factors from the egg jelly, sperm attractants from
the eggs, and decapacitation factors from the seminal plasma. The factors controlling sperm fertility are myriad and species
specific; they may be peptides, sugar chains, or small organic compounds. Nevertheless, the fundamental mechanisms underlying
fertilization must be common among all animals; increase in [Ca2+]i triggers all the steps in the process of fertilization, and cAMP plays important roles in many steps. Elucidating the dynamic
functional and morphological changes in sperm cells is important for understanding the regulation of fertilization. Here,
we introduce the diversity and generality of the control of sperm fertility.
Received 28 April 2008; received after revision 13 June 2008; accepted 17 June 2008 相似文献
16.
Diversity of Cl− Channels 总被引:5,自引:0,他引:5
Cl− channels are widely found anion pores that are regulated by a variety of signals and that play various roles. On the basis
of molecular biologic findings, ligand-gated Cl− channels in synapses, cystic fibrosis transmembrane conductors (CFTRs) and ClC channel types have been established, followed
by bestrophin and possibly by tweety, which encode Ca2+-activated Cl− channels. The ClC family has been shown to possess a variety of functions, including stabilization of membrane potential,
excitation, cellvolume regulation, fluid transport, protein degradation in endosomal vesicles and possibly cell growth. The
molecular structure of Cl− channel types varies from 1 to 12 transmembrane segments. By means of computer-based prediction, functional Cl− channels have been synthesized artificially, revealing that many possible ion pores are hidden in channel, transporter or
unidentified hydrophobic membrane proteins. Thus, novel Cl−-conducting pores may be occasionally discovered, and evidence from molecular biologic studies will clarify their physiologic
and pathophysiologic roles.
Received 28 July 2005; received after revision 25 August 2005; accepted 21 September 2005 相似文献
17.
Muñoz U Bartolomé F Esteras N Bermejo-Pareja F Martín-Requero A 《Cellular and molecular life sciences : CMLS》2008,65(21):3507-3519
It has been proposed that neuroinflammation, among other factors, may trigger an aberrant neuronal cell cycle re-entry leading
to neuronal death. Cell cycle disturbances are also detectable in peripheral cells from Alzheimer’s disease (AD) patients.
We previously reported that the anti-inflammatory 15- deoxy-Δ12,14-prostaglandin J
2 (15d-PGJ
2) increased the cellular content of the cyclin-dependent kinase inhibitor p27, in lymphoblasts from AD patients. This work
aimed at elucidating the mechanisms of 15d-PGJ
2-induced p27 accumulation. Phosphorylation, half-life, and the nucleo-cytoplasmic traffic of p27 protein were altered by 15d-PGJ2
by mechanisms dependent on PI3K/Akt activity. 15d-PGJ
2 prevents the calmodulin-dependent Akt overactivation in AD lymphoblasts by blocking its binding to the 85-kDa regulatory
subunit of PI3K. These effects of 15d-PGJ
2 were not mimicked by 9,10-dihydro-15-deoxy-Δ12,14- prostaglandin J
2, suggesting that 15d-PGJ
2 acts independently of peroxisome proliferator-activated receptor γ activation and that the α,β-unsaturated carbonyl group
in the cyclopentenone ring of 15d-PGJ
2 is a requisite for the observed effects.
Received 14 July 2008; received after revision 2 September 2008; accepted 12 September 2008 相似文献
18.
Neuronal Kv7 channels underlie a voltage-gated non-inactivating potassium current known as the M-current. Due to its particular characteristics, Kv7 channels show pronounced control over the excitability of neurons. We will discuss various factors that have been shown to drastically alter the activity of this channel such as protein and phospholipid interactions, phosphorylation, calcium, and numerous neurotransmitters. Kv7 channels locate to key areas for the control of action potential initiation and propagation. Moreover, we will explore the dynamic surface expression of the channel modulated by neurotransmitters and neural activity. We will also focus on known principle functions of neural Kv7 channels: control of resting membrane potential and spiking threshold, setting the firing frequency, afterhyperpolarization after burst firing, theta resonance, and transient hyperexcitability from neurotransmitter-induced suppression of the M-current. Finally, we will discuss the contribution of altered Kv7 activity to pathologies such as epilepsy and cognitive deficits. 相似文献
19.
K. Shikama 《Cellular and molecular life sciences : CMLS》1985,41(6):701-706
Summary The iron(II)-dioxygen bond in myoglobin and hemoglobin is a subject of wide interest. Studieas range from examinations of physical-chemical properties dependent on electronic structure, to investigations of stability as a function of oxygen supply. Stability properties are of particular importance in vivo, since the oxygenated form is known to be oxidized easily to the ferric form, which cannot be oxygenated and is therefore physiologically inactive.Kinetic and thermodynamic studies of the stability of native oxymyoglobin have revealed a new feature in FeO2 bonding. In vivo. the iron center is always subject to a nucleophilic attack of the water molecule or hydroxyl ion, which can enter the heme pocket from the surrounding solvent, and thereby irreversibly displace the bound dioxygen from MbO2 in the form of O
2
–
so that the iron is converted to the ferric form. A free energy diagram for the potential reactions of FeO2 visualizes myoglobin as a molecular structure that can provide in solution the delicate balance of kinetic and thermodynamic factors necessary to stabilize reversible oxygenation, as opposed to irreversible autoxidation to metmyoglobin. 相似文献
20.
Gap junctions (GJs) are composed of proteins that form a channel connecting the cytoplasm of adjacent cells. Connexins were
initially considered to be the only proteins capable of GJ formation. Another family of GJ proteins (innexins) were first
found in invertebrates and were proposed to be renamed pannexins after their orthologs were discovered in vertebrates. The
lack of both connexins and pannexins in the genomes of some metazoans suggests that other, still undiscovered GJ proteins
exist. In vertebrates, connexins and pannexins co-exist. Here we discuss whether vertebrate pannexins have a nonredundant
role in animal physiology. Pannexin channels appear to be suited for ATP and calcium signaling and play a role in the maintenance
of calcium homeostasis by mechanisms implicating both GJ and nonjunctional function. Suggested roles in the ischemic death
of neurons, schizophrenia, inflammation and tumor suppression have drawn much attention to exploring the molecular properties
and cellular functions of pannexins.
Received 22 April 2007; received after revision 9 September 2007; accepted 19 September 2007 相似文献