Acetylcholine Release at Neuromuscular Junctions of Adult Tottering Mice Is Controlled by N-(Cav2.2) and R-Type (Cav2.3) but Not L-Type (Cav1.2) Ca2+Channels

Pardo, Nicole E.; Hajela, Ravindra K.; Atchison, William D.

doi:10.1124/jpet.106.108670

Cited by 36 publications

(27 citation statements)

References 47 publications

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“…Preparations were continuously perfused with physiological saline at a rate of 1-5 ml/min, and were retreated with 2.5-4 mM m-conotoxin GIIIB for 15 minutes, after~60-90 minutes, to maintain contractile block. This allowed end-plate potentials (EPPs) to be recorded from intact myofibers without depressing ACh release (high [Mg 21 ], low [Ca 21 ]) or blocking postjunctional ACh receptors (d-tubocurarine) (Pardo et al, 2006). Separate preparations were used for each experiment, and a given hemidiaphragm received only one treatment.…”

Section: Methodsmentioning

confidence: 99%

“…Although mature mammalian motor nerve terminals contain almost exclusively P/Q-type VGCCs (Uchitel et al, 1992;Katz et al, 1995), under certain specific conditions, subtypes of VGCC that are not normally associated with acetylcholine (ACh) release at motor nerve terminals can assume control (Flink and Atchison, 2002;Urbano et al, 2003;Pagani et al, 2004;Pardo et al, 2006;Kaja et al, 2007a). Adaptation to loss of the a 1A -subunit obviously involves substitution of other a 1 -subunits; however, the impact of loss of a specific b-subunit, in this case b 4 , is less clear.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, the ability of R-type VGCCs to contribute to ACh release in lh mice was not tested. In adult tottering (tg) mice, in which the a 1A -subunit is mutated, R-type channels play a major role in regulating ACh release (Pardo et al, 2006), whereas in juvenile tg mice, R-type contribution is minor (15%) (Kaja et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…We hypothesized that P/Q-type channels would be replaced with other HVA VGCC subtypes, including L-(Ca v 1.2), N-, or R-type, as occurs when P/Q-type channels become dysfunctional (Qian and Noebels, 2000;Pardo et al, 2006;Kaja et al, 2007b) or decrease in number (Flink and Atchison, 2002;Nudler et al, 2003;Pagani et al, 2004), and that loss of b 4 would in turn be compensated by replacement with other b-subunits. The functional consequences of either a 1 -and/or b-subunit substitution could be responsible for the lh phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Age-Dependent Contribution of P/Q- and R-Type Ca²⁺Channels to Neuromuscular Transmission inLethargicMice

Molina-Campos

Atchison

2014

J Pharmacol Exp Ther

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b-Subunits of voltage-gated calcium channels (VGCCs) regulate assembly and membrane localization of the pore-forming a 1 -subunit and strongly influence channel function. b 4 -Subunits normally coassociate with a 1A -subunits which comprise P/Q-type (Ca v 2.1) VGCCs. These control acetylcholine (ACh) release at adult mammalian neuromuscular junctions (NMJs). The naturally occurring lethargic (lh) mutation of the b 4 -subunit in mice causes loss of the a 1 -binding site, possibly affecting P/Q-type channel expression or function, and thereby ACh release. End-plate potentials and miniature end-plate potentials were recorded at hemidiaphragm NMJs of 5-7-week and 3-5-month-old lh and wild-type (wt) mice. Sensitivity to antagonists of P/Q-[v-agatoxin IVA (v-Aga-IVA)], L-(nimodipine), N-(v-conotoxin GVIA), and R-type [C 192 H 274 N 52 O 60 S 7 (SNX-482)] VGCCs was compared in juvenile and adult lh and wt mice. Quantal content (m) of adult, but not juvenile, lh mice was reduced compared to wt. v-Aga-IVA (~60%) and SNX-482 (~45%) significantly reduced m in adult lh mice. Only Aga-IVA affected wt adults. In juvenile lh mice, v-Aga-IVA and SNX-482 decreased m by .75% and~20%, respectively. Neither v-conotoxin GVIA nor nimodipine affected ACh release in any group. Immunolabeling revealed a 1E and a 1A , b 1 , and b 3 staining at adult lh, but not wt NMJs. Therefore, in lh mice, when the b-subunit that normally coassociates with a 1A to form P/Q channels is missing, P/Q-type channels partner with other b-subunits. However, overall participation of P/Q-type channels is reduced and compensated for by R-type channels. R-type VGCC participation is age-dependent, but is less effective than P/Q-type at sustaining NMJ function.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Age-Dependent Contribution of P/Q- and R-Type Ca²⁺Channels to Neuromuscular Transmission inLethargicMice

Molina-Campos

Atchison

2014

J Pharmacol Exp Ther

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“…clone; Nishimune et al, 2004;Chen et al, 2011;Chand et al, 2015), mouse anti-SNAP25 at 1:5000 (Sigma; Sadakata et al, 2006;Hata et al, 2007), mouse anti-Syntaxin 1A at 1:500 (Sigma; clone HPC-1; Pardo et al, 2006), rabbit anti-Ca v 2.2 (N-type VGCC) at 1:1000 (Alomone; Pagani et al, 2004), rabbit anti-Ca v 2.1 (P/Q-type VGCC) at 1.500 (Alomone; (Alomone; Pagani et al, 2004), and rabbit anti-laminin-α4 (ID# 1100) at 1.500 and rabbit anti-laminin-α5 (ID# 8948) at 1.1000 (antibodies kindly provided by Professor Jeffrey Miner). For Chapter 4, EDL cryosections were stained for detection of laminin-α4 chain, while in Chapter 5, tibialis anterior (TA) muscle sections were stained for the detection of laminins-α4 and -α5.…”

Section: Section Immunohistochemistrymentioning

confidence: 99%

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Lee¹

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The proper development, maturation and maintenance of the neuromuscular junction (NMJ) are critical for ensuring efficient neurotransmission. Proteins found within the basal lamina of the synaptic cleft, namely the laminins family, are heavily involved in maintaining normal structure and function of the NMJ. In particular, individual laminin chains such as laminin-β2, -α4 and -α5 play essential roles in organisation and maintenance of the NMJ. These laminin chains interact together to form three synapse specific laminin heterotrimers; laminin-221 (α2β2γ1), laminin-421 (α4β2γ1) and laminin-521 (α5β2γ1).Laminin-β2 is the common laminin chain found in each of these synapse specific laminin heterotrimers. In-vitro it has been shown to play a key role in the organisation of the presynaptic elements at the NMJ via its interaction and clustering of the N-and P/Q-type voltage-gated calciums (VGCCs). During development of the NMJ, both N-and P/Q-type VGCCs are involved in mediating neurotransmitter release. As the NMJ matures, P/Q-type becomes the dominant channel involved in release while N-type takes on the role of fine-tuning calcium influx. Laminin-α4, on the other hand, ensures proper alignment of presynaptic active zones to postjunctional folds at the NMJ, with its loss resulting in misalignment of these specialisations. Furthermore, this laminin chain has been shown to be involved in the maintenance of the NMJ with the observation of premature ageing features at 6 months of age (6MO) in laminin-α4 deficient mice (lama4 NMJs.In conclusion, this thesis has identified the significant roles laminins-α4 and -β2 play at the NMJ during development, maturation and maintenance. Results suggest that laminin-β2 is not only an important regulator of the presynaptic maturation through the switching of VGCCs and clustering of P/Q-type VGCCs, but also equally important for maturation of the postsynaptic apparatus. Ipropose that laminin-β2 is important for the maturation of each component at the NMJ. The altered responses in transmission properties presented by aged wild-type NMJs which resembled adult lama4 -/-, preceded by altered expression of laminin-α4 chain, strongly suggest that laminin-α4 is not only important for maintaining proper alignment of pre-to postsynaptic NMJ, but also essentially important for maintaining a healthy adult NMJ. Finally, I observed early alterations in expression of laminin-α4 at the NMJs in diseased mouse model of ALS prior to any appearance of neuromotor impairment, suggesting a potential involvement of laminins in NMJ degeneration associated with neuromuscular disorders such as ALS.ii

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Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

et al. 2023

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Background The intercellular transmission of pathogenic proteins plays a crucial role in the progression of neurodegenerative diseases. Previous research has shown that the neuronal uptake of such proteins is activity‐dependent; however, the detailed mechanisms underlying activity‐dependent α‐synuclein transmission in Parkinson's disease remain unclear. Objective To examine whether α‐synuclein transmission is affected by Ca2+–calmodulin–calcineurin signaling in cultured cells and mouse models of Parkinson's disease. Methods Mouse primary hippocampal neurons were used to examine the effects of the modulation of Ca2+–calmodulin–calcineurin signaling on the neuronal uptake of α‐synuclein preformed fibrils. The effects of modulating Ca2+–calmodulin–calcineurin signaling on the development of α‐synuclein pathology were examined using a mouse model injected with α‐synuclein preformed fibrils. Results Modulation of Ca2+–calmodulin–calcineurin signaling by inhibiting voltage‐gated Ca2+ channels, calmodulin, and calcineurin blocked the neuronal uptake of α‐synuclein preformed fibrils via macropinocytosis. Different subtypes of voltage‐gated Ca2+ channel differentially contributed to the neuronal uptake of α‐synuclein preformed fibrils. In wild‐type mice inoculated with α‐synuclein preformed fibrils, we found that inhibiting calcineurin ameliorated the development of α‐synuclein pathology. Conclusion Our data suggest that Ca2+–calmodulin–calcineurin signaling modulates α‐synuclein transmission and has potential as a therapeutic target for Parkinson's disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Acetylcholine Release at Neuromuscular Junctions of Adult Tottering Mice Is Controlled by N-(Ca_v2.2) and R-Type (Ca_v2.3) but Not L-Type (Ca_v1.2) Ca²⁺Channels

Abstract: The mutation in the ␣ 1A

Cited by 36 publications

References 47 publications

Age-Dependent Contribution of P/Q- and R-Type Ca²⁺Channels to Neuromuscular Transmission inLethargicMice

Age-Dependent Contribution of P/Q- and R-Type Ca²⁺Channels to Neuromuscular Transmission inLethargicMice

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

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Acetylcholine Release at Neuromuscular Junctions of Adult Tottering Mice Is Controlled by N-(Cav2.2) and R-Type (Cav2.3) but Not L-Type (Cav1.2) Ca2+Channels

Abstract: The mutation in the ␣ 1A

Cited by 36 publications

References 47 publications

Age-Dependent Contribution of P/Q- and R-Type Ca2+Channels to Neuromuscular Transmission inLethargicMice

Age-Dependent Contribution of P/Q- and R-Type Ca2+Channels to Neuromuscular Transmission inLethargicMice

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Ca2+–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission

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Product

Resources

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Acetylcholine Release at Neuromuscular Junctions of Adult Tottering Mice Is Controlled by N-(Ca_v2.2) and R-Type (Ca_v2.3) but Not L-Type (Ca_v1.2) Ca²⁺Channels

Age-Dependent Contribution of P/Q- and R-Type Ca²⁺Channels to Neuromuscular Transmission inLethargicMice

Age-Dependent Contribution of P/Q- and R-Type Ca²⁺Channels to Neuromuscular Transmission inLethargicMice

Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission