Computational modeling predicts ephemeral acidic microdomains in the glutamatergic synaptic cleft

Feghhi, Touhid; Hernandez, Roberto X.; Stawarski, Michał; Thomas, Connon I.; Kamasawa, Naomi; Lau, Andy T. Y.; Macleod, Gregory T.

doi:10.1016/j.bpj.2021.11.011

Cited by 7 publications

(9 citation statements)

References 94 publications

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“…Taken together, the findings that [H + ] o activates TH in catecholaminergic cells may have important physiological consequences. First, transient synaptic cleft acidification due to the release of acidic synaptic content has been previously documented in mammalian cone photoreceptors, − glutaminergic, and GABA neurons . For example, rapid reduction of synaptic cleft pH by about 0.2–0.6 units due to the release of acidic synaptic content in mammalian cone photoreceptors has been reported. − Other studies have shown that high-frequency stimulation transiently acidifies hippocampal brain slices due to the release of acidic synaptic content. − Thus, it is conceivable that protons from the exocytotic release of acidic content of synaptic vesicles (∼pH 5.2 to 5.7) ,− could transiently acidify the synaptic cleft area in catecholaminergic neurons causing the activation of TH.…”

Section: Resultsmentioning

confidence: 99%

“…In summary, the present studies provide strong evidence to support that [H + ] o is a novel extracellular signal for TH activation in catecholaminergic cells, which is distinct from the widely accepted view that depolarization and/or electrical stimulation-associated increase in intracellular Ca 2+ Taken together, the findings that [H + ] o activates TH in catecholaminergic cells may have important physiological consequences. First, transient synaptic cleft acidification due to the release of acidic synaptic content has been previously documented in mammalian cone photoreceptors, 25−27 glutaminergic, 49 and GABA neurons. 26 For example, rapid reduction of synaptic cleft pH by about 0.2−0.6 units due to the release of acidic synaptic content in mammalian cone photoreceptors has been reported.…”

Section: T H I S C O N T E N T Imentioning

confidence: 99%

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Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

Eldani

Truong

et al. 2023

ACS Chem. Neurosci.

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Tyrosine hydroxylase catalyzes the rate-limiting step in the catecholamine biosynthetic pathway. Short-term TH activity is proposed to be regulated by the phosphorylation/dephosphorylation of regulatory domains Ser 40, 31, and/or 19 in response to membrane depolarization coupled increase in intracellular Ca 2+ . Here, we present in situ evidence to support that extracellular H + ions ([H + ] o ) are an intracellular or extracellular Ca 2+ -independent novel signal for TH activation in catecholaminergic MN9D and PC12 cells. [H + ] o -mediated TH activation is a short-term process coupled with a Na +independent Cl − /HCO 3 − exchanger-mediated increase of intracellular hydrogen ions ([H + ] i ). While extracellular Ca 2+ is not required for [H + ] o -mediated TH activation, [H + ] o does not increase the cytosolic Ca 2+ levels in neuronal or non-neuronal cells in the presence or absence of extracellular Ca 2+ . Although [H + ] o -mediated TH activation is associated with a significant increase in Ser 40 phosphorylation, major protein kinases proposed to be responsible for this process appear to be not involved. However, we have not been able to identify the protein kinase(s) involved in [H + ] o -mediated phosphorylation of TH at present. Studies with a panphosphatase inhibitor, okadaic acid (OA), appear to indicate that the inhibition of phosphatase activities may not play a significant role in H + -mediated activation of TH. The relevance of these findings to the physiological TH activation mechanism and hypoxia, ischemia, and trauma-induced selective dopaminergic neural death is being discussed in this paper.

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Section: Resultsmentioning

confidence: 99%

Section: T H I S C O N T E N T Imentioning

confidence: 99%

Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

Eldani

Truong

et al. 2023

ACS Chem. Neurosci.

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“…This novel function of aSN is relevant to calcium homeostasis of neurons and specifically presynaptic compartments, where PMCA plays a key role in calcium homeostasis; however, potentially it affects also the extracellular environment, where the exchange of each calcium ion for two protons by PMCA leads to transient alkalinization of nanodomains at the synaptic cleft with consequences to postsynaptic NMDA receptor fluxes (Chen & Chesler, 2015; Feghhi et al , 2021). Furthermore, the activated proton import of PMCA may be important for neutralization of an acidified environment at the synaptic cleft with large release activity of acidified neurotransmitter vesicles.…”

Section: Discussionmentioning

confidence: 99%

Monomeric α‐synuclein activates the plasma membrane calcium pump

Kowalski,

Betzer,

Larsen

et al. 2023

The EMBO Journal

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Alpha‐synuclein (aSN) is a membrane‐associated and intrinsically disordered protein, well known for pathological aggregation in neurodegeneration. However, the physiological function of aSN is disputed. Pull‐down experiments have pointed to plasma membrane Ca2+‐ATPase (PMCA) as a potential interaction partner. From proximity ligation assays, we find that aSN and PMCA colocalize at neuronal synapses, and we show that calcium expulsion is activated by aSN and PMCA. We further show that soluble, monomeric aSN activates PMCA at par with calmodulin, but independent of the autoinhibitory domain of PMCA, and highly dependent on acidic phospholipids and membrane‐anchoring properties of aSN. On PMCA, the key site is mapped to the acidic lipid‐binding site, located within a disordered PMCA‐specific loop connecting the cytosolic A domain and transmembrane segment 3. Our studies point toward a novel physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA.

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“…We show here that native, monomeric aSN exerts a strongly activating effect on PMCA, whereas oligomeric aSN was weaker and perhaps even just ascribed to the small amount of released monomer (Figure S2) . This novel function of aSN is relevant to calcium homeostasis of neurons and specifically presynaptic compartments; however, potentially affects also extracellular environment, where the exchange of each calcium ion for two protons by PMCA leads to formation of transient alkaline nanodomains of the synaptic cleft with consequences to postsynaptic NMDAR fluxes (Chen and Chesler, 2015; Feghhi et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…This novel function of aSN is relevant to calcium homeostasis of neurons and specifically presynaptic compartments; however, potentially affects also extracellular environment, where the exchange of each calcium ion for two protons by PMCA leads to formation of transient alkaline nanodomains of the synaptic cleft with consequences to postsynaptic NMDAR fluxes (Chen & Chesler, 2015; Feghhi et al , 2021).…”

Section: Discussionmentioning

confidence: 99%

Monomeric α-Synuclein activates the Plasma Membrane Calcium Pump

Kowalski

Betzer

Larsen

et al. 2022

Preprint

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Alpha-synuclein (aSN) is a membrane-associated and intrinsically disordered protein, well-known for pathological aggregation in neurodegeneration. The physiological function of aSN however is disputed. Pull-down experiments have pointed to plasma membrane Ca2+-ATPase (PMCA) as a potential interaction partner. From proximity ligation assays we find here that aSN and PMCA colocalize at neuronal synapses, and that calcium expulsion is activated by aSN and PMCA. From PMCA activity studies we show that soluble, monomeric aSN activates PMCA at par with calmodulin, yet independent of the autoinhibitory domain of PMCA, but highly dependent on acidic phospholipids and the membrane-anchoring N-terminus of aSN. On the PMCA molecule, the interaction site is mapped to the acidic lipid-binding site, located within a PMCA-specific linker region connecting the cytosolic A domain and transmembrane segment 3. Our studies point towards a physiological role of monomeric aSN as a stimulator of calcium clearance in neurons through activation of PMCA

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Computational modeling predicts ephemeral acidic microdomains in the glutamatergic synaptic cleft

Cited by 7 publications

References 94 publications

Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

Monomeric α‐synuclein activates the plasma membrane calcium pump

Monomeric α-Synuclein activates the Plasma Membrane Calcium Pump

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Computational modeling predicts ephemeral acidic microdomains in the glutamatergic synaptic cleft

Cited by 7 publications

References 94 publications

Extracellular H+ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

Extracellular H+ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

Monomeric α‐synuclein activates the plasma membrane calcium pump

Monomeric α-Synuclein activates the Plasma Membrane Calcium Pump

Contact Info

Product

Resources

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Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells