Activation of PAC1 Receptors in Rat Cerebellar Granule Cells Stimulates Both Calcium Mobilization from Intracellular Stores and Calcium Influx through N-Type Calcium Channels

Basille-Dugay, Magali; Vaudry, Hubert; Fournier, Alain; Gonzalez, Bruno J.; Vaudry, David

doi:10.3389/fendo.2013.00056

Cited by 7 publications

(6 citation statements)

References 76 publications

(81 reference statements)

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“…Our results demonstrate that intracellular basal Ca 2+ was not increased by GDF-15 treatment; however, [Ca 2+ ] i in response to membrane depolarization and nifedipine-sensitive I Ca were up-regulated, suggesting the involvement of L-type Ca 2+ channels, although we cannot exclude the possibility that nifedipine-insensitive Ca 2+ channels or N-, P/Q- or R-type Ca 2+ channels were also modulated by GDF-15. A study of rat CGNs indicated that administration of PACAP (pituitary adenylate cyclase-activating polypeptide) induced a rapid rise in [Ca 2+ ] i and thereby stimulated Ca 2+ influx through N-type but not L-type Ca 2+ channels [ 31 ]. This difference may be explained by the fact that PACAP affects basal [Ca 2+ ] i , but not the response to membrane depolarization.…”

Section: Discussionmentioning

confidence: 99%

GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons

Wang

et al. 2016

Biochemical Journal

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GDF-15 (growth/differentiation factor 15) is a novel member of the TGF (transforming growth factor)-β superfamily that has critical roles in the central and peripheral nervous systems. We reported previously that GDF-15 increased delayed rectifier outward K+ currents and Kv2.1 α subunit expression through TβRII (TGF-β receptor II) to activate Src kinase and Akt/mTOR (mammalian target of rapamycin) signalling in rat CGNs (cerebellar granule neurons). In the present study, we found that treatment of CGNs with GDF-15 for 24 h increased the intracellular Ca2+ concentration ([Ca2+]i) in response to membrane depolarization, as determined by Ca2+ imaging. Whole-cell current recordings indicated that GDF-15 increased the inward Ca2+ current (ICa) without altering steady-state activation of Ca2+ channels. Treatment with nifedipine, an inhibitor of L-type Ca2+ channels, abrogated GDF-15-induced increases in [Ca2+]i and ICa. The GDF-15-induced increase in ICa was mediated via up-regulation of the Cav1.3 α subunit, which was attenuated by inhibiting Akt/mTOR and ERK (extracellular-signal-regulated kinase) pathways and by pharmacological inhibition of Src-mediated TβRII phosphorylation. Given that Cav1.3 is not only a channel for Ca2+ influx, but also a transcriptional regulator, our data confirm that GDF-15 induces protein expression via TβRII and activation of a non-Smad pathway, and provide novel insight into the mechanism of GDF-15 function in neurons.

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Section: Discussionmentioning

confidence: 99%

GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons

Wang

et al. 2016

Biochemical Journal

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“…30C). These effects are in agreement with previous reports documenting PACAP-mediated increase in intracellular Ca 2+ levels [172,[199][200][201][202]. This result indicated that PACAP38 could enhance increased excitatory activity and Ca 2+ influx in neurons, which could be resulted from downregulation of Kv4.2 channels, as observed previously in chapter II.…”

Section: Pacap-mediated Dephosphorylation Of the Kv21 Channel Is Indsupporting

confidence: 93%

“…These kinases have been previously shown to phosphorylate glutamatergic NMDA and AMPA receptors leading to their enhanced activation [119][120][121][122]181]. In addition, PACAP can activate both L-type and N-type calcium channels which are abundantly expressed on neuronal dendrites and soma [199,214]. All these mechanisms in addition to Kv4.2 phosphorylation can result in increased dendritic and overall neuronal excitability leading to increases in electrical signal input to the soma.…”

Section: Discussionmentioning

confidence: 99%

“…In the previous chapters I have shown that PACAP can activate the Gα S -mediated signaling cascade. In addition, PACAP upon binding to its receptor PAC1 can also elevate calcium (Ca 2+ ) levels both by release from intracellular stores in a Gα q -dependent manner, as well as by influx through voltage-gated Ca 2+ channels [199][200][201][202]. In the previous chapter I showed that PACAP38 could reduce Kv4.2-mediated I A currents, which could contribute to and increase in the intrinsic excitability of neurons.…”

Section: Figure 19 Pacap38 Does Not Alter Voltage-dependence Of Kv4mentioning

confidence: 99%

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Phosphoregulation of somatodendritic voltage-gated potassium channels by pituitary adenylate cyclase-activating polypeptide

Gupte¹

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____________________________________________ Yuriy M. Usachevii To Papa-grandfather, extraordinary teacher and a life-long student. And to Aaji who always stood by him.iii The important thing is not to stop questioning. Curiosity has its own reason for existing.-Albert Einstein iv ACKNOWLEDGEMENTS First and foremost I would like to thank my advisor Dr. D. P. Mohapatra not only for accepting me in his lab but also for guiding me each step of the way over the past four years. He gave me the freedom to choose a research topic of my interest and was always open to questions. Most of all, I would like to thank him for believing in me even at times when I did not believe in myself.I would also like to thank all the members of my dissertation committee -Dr.guidance and suggestions have helped make this study a more cohesive one. Their different scientific backgrounds have helped me look at my project from multiple perspectives. Next I would like to thank all the current and past members of the Mohapatra lab who have helped shape my graduate life and scientific experience. A big thank you goes out to Andrew Shepherd for teaching me most of the lab skills I know and always patiently answering all my questions no matter how silly they are! Also for helping me perform immunohistochemical staining on brain sections. And lastly but most importantly for getting me hooked on to all his delicious baked goodies! I am also very thankful to Suraj Kadunganattil for helping me with my experiments when I was short on time while writing my thesis. I would like to thank Lipin Loo for teaching me electrophysiology and Aaron Mickle, Thomas James, Satya Murty Tadinada and Ajit Tiwari for their invaluable suggestions during lab meetings and seminars. I am also grateful to my colleagues from other labs especially Andy Slupe and Ron Merrill from the Strack lab. Andy Slupe for teaching me hippocampal neuron cultures v along with Andrew and Ron for performing the metabolic labelling experiments. Thanks to all members of the Usachev lab for their inputs and suggestions during lab meetings. I would also like to thank my academic advisors Dr. Barry Kasson and Dr. Fred Quelle for their help in registering for courses each semester and for their guidance during my comps. Thanks to the Pharmacology administrative staff Linda, Lisa, Kate and Vicki for booking rooms and ensuring that all the paperwork always went through smoothly. Lastly, big thanks to my family and friends who have been my biggest support system. My parents Prashant Gupte and Sanyogita Gupte for giving me the ability to pursue my career goals in a foreign country. To my mom for staying up with me late at night as I laboured at my thesis and for helping me insert references and format the document. I am also grateful for my grandmother who ensured that I was well-fed even though I was losing sleep over my thesis writing. My husband Aniruddha Shukla has been extremely patient during my PhD journey, in spite of having to stay apart from each other for over a year. To my other set of pare...

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“…It has been demonstrated that PACAP promotes the increase of intracellular calcium from intracellular stores and calcium influx through calcium channels. 45,46 The mobilization of calcium allows the activation of CaMKIV, and then the increase of CREB activity. 47,48 More recently, it has been shown that PACAPmediated protective effect is also through the release of tissue plasminogen activator.…”

Section: Molecular Pathways Related To the Neuroprotection Of Cgnsmentioning

confidence: 99%

Delineating the Factors and Cellular Mechanisms Involved in the Survival of Cerebellar Granule Neurons

Xifró

Rodríguez‐Álvarez

2015

Cerebellum

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Cerebellar granule neurons (CGNs) constitute the most abundant neuronal population in the mammalian brain. Their postnatal generation and the feasibility to induce their apoptotic death in vitro make them an excellent model to study the effect of several neurotransmitters and neurotrophins. Here, we first review which factors are involved in the generation and proliferation of CGNs in the external granule layer (EGL) and in the regulation of their differentiation and migration to internal granule layer (IGL). Special attention was given to the role of several neurotrophins and the NMDA subtype of glutamate receptor. Then, using the paradigm of potassium deprivation in cultured CGNs, we address several extracellular factors that promote the survival of CGNs, with particular emphasis on the cellular mechanisms. The role of specific protein kinases leading to the regulation of transcription factors and recent data involving the small G protein family is also discussed. Finally, the participation of some members of Bcl-2 family and the inhibition of mitochondria-related apoptotic pathway is also considered. Altogether, these studies evidence that CGNs are a key model to understand the development and the survival of neuronal populations.

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Activation of PAC1 Receptors in Rat Cerebellar Granule Cells Stimulates Both Calcium Mobilization from Intracellular Stores and Calcium Influx through N-Type Calcium Channels

Cited by 7 publications

References 76 publications

GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons

GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons

Phosphoregulation of somatodendritic voltage-gated potassium channels by pituitary adenylate cyclase-activating polypeptide

Delineating the Factors and Cellular Mechanisms Involved in the Survival of Cerebellar Granule Neurons

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