scholarly journals Regulation of longevity by depolarization-induced activation of PLC-β–IP3R signaling in neurons

2021 ◽  
Vol 118 (16) ◽  
pp. e2004253118
Author(s):  
Ching-On Wong ◽  
Nicholas E. Karagas ◽  
Jewon Jung ◽  
Qiaochu Wang ◽  
Morgan A. Rousseau ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Potential ◽  
Neuronal Excitability ◽  
Atp Synthesis ◽  
Inositol Trisphosphate Receptor ◽  
Atp Production ◽  
Glutamatergic Neurons ◽  
Reciprocal Influence ◽  
Underlying Mechanisms ◽  
Trisphosphate Receptor

Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP3R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β–IP3R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP3Rs. Manipulations that either lowered PLC-β/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β–IP3R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca2+ overload.

scholarly journals Extraocular muscle function is impaired in ryr3−/− mice

2019 ◽  
Vol 151 (7) ◽  
pp. 929-943 ◽  
Author(s):  
Jan Eckhardt ◽  
Christoph Bachmann ◽  
Marijana Sekulic-Jablanovic ◽  
Volker Enzmann ◽  
Ki Ho Park ◽  
...  
Keyword(s):  
Muscle Contraction ◽  
Ryanodine Receptor ◽  
Muscle Function ◽  
Extraocular Muscle ◽  
Calcium Release ◽  
Neuronal Excitability ◽  
Extraocular Muscles ◽  
Inositol Trisphosphate Receptor ◽  
Physiological Processes ◽  
Trisphosphate Receptor

Calcium is an ubiquitous second messenger mediating numerous physiological processes, including muscle contraction and neuronal excitability. Ca2+ is stored in the ER/SR and is released into the cytoplasm via the opening of intracellular inositol trisphosphate receptor and ryanodine receptor calcium channels. Whereas in skeletal muscle, isoform 1 of the RYR is the main channel mediating calcium release from the SR leading to muscle contraction, the function of ubiquitously expressed ryanodine receptor 3 (RYR3) is far from clear; it is not known whether RYR3 plays a role in excitation–contraction coupling. We recently reported that human extraocular muscles express high levels of RYR3, suggesting that such muscles may be useful to study the function of this isoform of the Ca2+ channel. In the present investigation, we characterize the visual function of ryr3−/− mice. We observe that ablation of RYR3 affects both mechanical properties and calcium homeostasis in extraocular muscles. These changes significantly impact vision. Our results reveal for the first time an important role for RYR3 in extraocular muscle function.

scholarly journals Evidence for the involvement of a small subregion of the endoplasmic reticulum in the inositol trisphosphate receptor-induced activation of Ca2+ inflow in rat hepatocytes

1999 ◽  
Vol 341 (2) ◽  
pp. 401 ◽  
Author(s):  
Roland B. GREGORY ◽  
Robert A. WILCOX ◽  
Leise A. BERVEN ◽  
Nicole C.R. VAN STRATEN ◽  
Gijs A. VAN DER MAREL ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Inositol Trisphosphate ◽  
Rat Hepatocytes ◽  
Inositol Trisphosphate Receptor ◽  
Trisphosphate Receptor

scholarly journals Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin

2015 ◽  
Vol 309 (8) ◽  
pp. F731-F743 ◽  
Author(s):  
Shankar Munusamy ◽  
Jussara M. do Carmo ◽  
Jonathan P. Hosler ◽  
John E. Hall
Keyword(s):  
Endoplasmic Reticulum ◽  
Oxidative Damage ◽  
Er Stress ◽  
Renal Injury ◽  
Atp Synthesis ◽  
Atp Production ◽  
Kidney Mitochondria ◽  
Atp Levels ◽  
Melanocortin 4 Receptor ◽  
Induced Changes

We investigated obesity-induced changes in kidney lipid accumulation, mitochondrial function, and endoplasmic reticulum (ER) stress in the absence of hypertension, and the potential role of leptin in modulating these changes. We compared two normotensive genetic mouse models of obesity, leptin-deficient ob/ob mice and hyperleptinemic melanocortin-4 receptor-deficient mice (LoxTB MC4R−/−), with their respective lean controls. Compared with controls, ob/ob and LoxTB MC4R−/− mice exhibit significant albuminuria, increased creatinine clearance, and high renal triglyceride content. Renal ATP levels were decreased in both obesity models, and mitochondria isolated from both models showed alterations that would lower mitochondrial ATP production. Mitochondria from hyperleptinemic LoxTB MC4R−/− mice kidneys respired NADH-generating substrates (including palmitate) at lower rates due to an apparent decrease in complex I activity, and these mitochondria showed oxidative damage. Kidney mitochondria of leptin-deficient ob/ob mice showed normal rates of respiration with no evidence of oxidative damage, but electron transfer was partially uncoupled from ATP synthesis. A fourfold induction of C/EBP homologous protein (CHOP) expression indicated induction of ER stress in kidneys of hyperleptinemic LoxTB MC4R−/− mice. In contrast, ER stress was not induced in kidneys of leptin-deficient ob/ob mice. Our findings show that obesity, in the absence of hypertension, is associated with renal dysfunction in mice but not with major renal injury. Alterations to mitochondria that lower cellular ATP levels may be involved in obesity-induced renal injury. The type and severity of mitochondrial and ER dysfunction differs depending upon the presence or absence of leptin.

Mitochondrial Regulation of Calcium in the Avian Cochlear Nucleus

1997 ◽  
Vol 78 (4) ◽  
pp. 1928-1934 ◽  
Author(s):  
Sam P. Mostafapour ◽  
Edward A. Lachica ◽  
Edwin W Rubel
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Cochlear Nucleus ◽  
Mitochondrial Membrane ◽  
Atp Synthesis ◽  
Cytosolic Calcium ◽  
Mitochondrial Regulation ◽  
Mitochondrial Number ◽  
And Function

Mostafapour, Sam P., Edward A. Lachica, and Edwin W Rubel. Mitochondrial regulation of calcium in the avian choclear nucleus. J. Neurophysiol. 78: 1928–1934, 1997. The role of mitochondria and the endoplasmic reticulum in buffering [Ca2+]i in response to imposed calcium loads in neurons of the chick cochlear nucleus, nucleus magnocellularis (NM), was examined. Intracellular calcium concentrations were measured using fluorometric videomicroscopy. After depolarization with 125 mM KCl, NM neurons demonstrate an increase in [Ca2+]i that returns to near-basal levels within 6 min. Addition of the protonophore carbonylcyanide m-chlorophenylhydrazone (CCCP) dissipated the mitochondrial membrane potential, as evidenced by increased fluorescence when cells were loaded with rhodamine-123. Two micromolar CCCP had minimal effect on baseline [Ca2+]i. However, 2 or 10 μM CCCP interfered with the ability of NM cells to buffer [Ca2+]i in response to KCl depolarization without significantly affecting peak [Ca2+]i. Oligomycin also interfered with postdepolarization regulation of [Ca2+]i, but blocked late (7–8 min postdepolarization) increases in [Ca2+]i caused by CCCP. Thapsigargin had no effect on baseline, peak, or postdepolarization [Ca2+]i in NM cells. These results suggest that normal mitochondrial membrane potential and ATP synthesis play an important role in buffering [Ca2+]i in response to imposed calcium loads in NM neurons. Furthermore, the endoplasmic reticulum does not appear to play a significant role in either of these processes. Thus increases in mitochondrial number and function noted in NM cells after deafferentation may represent an adaptive response to an increased cytosolic calcium load.

Targeting Dinitrophenol to Mitochondria: Limitations to the Development of a Self-limiting Mitochondrial Protonophore

2006 ◽  
Vol 26 (3) ◽  
pp. 231-243 ◽  
Author(s):  
Frances H. Blaikie ◽  
Stephanie E. Brown ◽  
Linda M. Samuelsson ◽  
Martin D. Brand ◽  
Robin A. J. Smith ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Membrane Potential ◽  
Oxidative Phosphorylation ◽  
Atp Synthesis ◽  
Proton Leak ◽  
Protonmotive Force ◽  
Inner Membrane ◽  
Atp Production ◽  
Mitochondrial Inner Membrane ◽  
Predominant Component

The protonmotive force (Δp) across the mitochondrial inner membrane drives ATP synthesis. In addition, the energy stored in Δp can be dissipated by proton leak through the inner membrane, contributing to basal metabolic rate and thermogenesis. Increasing mitochondrial proton leak pharmacologically should decrease the efficiency of oxidative phosphorylation and counteract obesity by enabling fatty acids to be oxidised with decreased ATP production. While protonophores such as 2,4-dinitrophenol (DNP) increase mitochondrial proton leak and have been used to treat obesity, a slight increase in DNP concentration above the therapeutically effective dose disrupts mitochondrial function and leads to toxicity. Therefore we set out to develop a less toxic protonophore that would increase proton leak significantly at high Δp but not at low Δp. Our design concept for a potential self-limiting protonophore was to couple the DNP moiety to the lipophilic triphenylphosphonium (TPP) cation and this was achieved by the preparation of 3-(3,5-dinitro-4-hydroxyphenyl)propyltriphenylphosphonium methanesulfonate (MitoDNP). TPP cations accumulate within mitochondria driven by the membrane potential (Δψ), the predominant component of Δp. Our hypothesis was that MitoDNP would accumulate in mitochondria at high Δψ where it would act as a protonophore, but that at lower Δψ the accumulation and uncoupling would be far less. We found that MitoDNP was extensively taken into mitochondria driven by Δψ. However MitoDNP did not uncouple mitochondria as judged by its inability to either increase respiration rate or decrease Δψ. Therefore MitoDNP did not act as a protonophore, probably because the efflux of deprotonated MitoDNP was inhibited.

scholarly journals Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins

2020 ◽  
Author(s):  
Colin H. Peters ◽  
Mallory E. Myers ◽  
Julie Juchno ◽  
Charlie Haimbaugh ◽  
Hicham Bichraoui ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Ion Channels ◽  
Membrane Protein ◽  
Cyclic Nucleotide ◽  
Voltage Dependence ◽  
Cardiac Pacemaker ◽  
Pacemaker Cells ◽  
Inositol Trisphosphate Receptor ◽  
Kinase Substrate ◽  
Trisphosphate Receptor

AbstractIon channels in excitable cells function in macromolecular complexes in which auxiliary proteins modulate the biophysical properties of the pore-forming subunits. Hyperpolarization-activated, cyclic nucleotide-sensitive HCN4 channels are critical determinants of membrane excitability in cells throughout the body, including thalamocortical neurons and cardiac pacemaker cells. We previously showed that the properties of HCN4 channels differ dramatically in different cell types, possibly due to the endogenous expression of auxiliary proteins. Here, we report the discovery of a family of endoplasmic reticulum transmembrane proteins that interact with and modulate HCN4. Lymphoid-restricted membrane protein (LRMP, Jaw1) and inositol trisphosphate receptor-associated guanylate kinase substrate (IRAG, Mrvi1, Jaw1L) are homologous proteins with small ER luminal domains and large cytoplasmic domains. Despite their homology, LRMP and IRAG have distinct effects on HCN4. LRMP is a loss-of-function modulator that inhibits the canonical depolarizing shift in the voltage-dependence of HCN4 activation in response to binding of cAMP. In contrast, IRAG causes a gain of HCN4 function by depolarizing the basal voltage-dependence of activation in the absence of cAMP. The mechanisms of action of LRMP and IRAG are novel; they are independent of trafficking and cAMP binding, and they are specific to the HCN4 isoform. We also found that IRAG is highly expressed in the mouse sinoatrial node where computer modeling predicts that its presence increases HCN4 availability. Our results suggest important roles for LRMP and IRAG in regulation of cellular excitability and as tools for advancing mechanistic understanding of HCN4 channel function.Significance statementThe pore-forming subunits of ion channels are regulated by auxiliary interacting proteins. Hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channels are critical determinants of electrical excitability in many types of cells including neurons and cardiac pacemaker cells. Here we report the discovery of two novel HCN4 regulatory proteins. Despite their homology, the two proteins — lymphoid-restricted membrane protein (LRMP) and inositol trisphosphate receptor-associated guanylate kinase substrate (IRAG) — have opposing effects on HCN4, causing loss- and gain-of-function, respectively. LRMP and IRAG are expected to play critical roles in regulation of physiological processes ranging from wakefulness to heart rate through their modulation of HCN4 channel function.

Sign in / Sign up

Export Citation Format

Share Document