BoNT/A in the Urinary Bladder—More to the Story Than Silencing of Cholinergic Nerves

Botulinum neurotoxin (BoNT/A) is an FDA and NICE approved second-line treatment for overactive bladder (OAB) in patients either not responsive or intolerant to anti-cholinergic drugs. BoNT/A acts to weaken muscle contraction by blocking release of the neurotransmitter acetyl choline (ACh) at neuromuscular junctions. However, this biological activity does not easily explain all the observed effects in clinical and non-clinical studies. There are also conflicting reports of expression of the BoNT/A protein receptor, SV2, and intracellular target protein, SNAP-25, in the urothelium and bladder. This review presents the current evidence of BoNT/A’s effect on bladder sensation, potential mechanisms by which it might exert these effects and discusses recent advances in understanding the action of BoNT in bladder tissue.

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Identification of Fibroblast Growth Factor Receptor 3 (FGFR3) as a Protein Receptor for Botulinum Neurotoxin Serotype A (BoNT/A)

PLoS Pathogens ◽

10.1371/journal.ppat.1003369 ◽

2013 ◽

Vol 9 (5) ◽

pp. e1003369 ◽

Cited By ~ 45

Author(s):

Birgitte P. S. Jacky ◽

Patton E. Garay ◽

Jérôme Dupuy ◽

Jeremy B. Nelson ◽

Brian Cai ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Botulinum Neurotoxin ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Fibroblast Growth ◽

Serotype A ◽

Protein Receptor ◽

Botulinum Neurotoxin Serotype A

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Capsaicin Protects Mouse Neuromuscular Junctions From The Paralytic Effects Of Botulinum Neurotoxin A

Biophysical Journal ◽

10.1016/j.bpj.2008.12.1323 ◽

2009 ◽

Vol 96 (3) ◽

pp. 268a

Author(s):

Baskaran Thyagarajan ◽

Natalia Krivitskaya ◽

Kormakur Hognason ◽

Joseph G. Potian ◽

Joseph J. McArdle

Keyword(s):

Botulinum Neurotoxin ◽

Neuromuscular Junctions ◽

Botulinum Neurotoxin A

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Current Evidence on the Unit Equivalence of Different Botulinum Neurotoxin A Formulations and Recommendations for Clinical Practice in Dermatology

Dermatologic Surgery ◽

10.1111/j.1524-4725.2008.34375.x ◽

2009 ◽

Vol 35 (1) ◽

pp. 1-8 ◽

Cited By ~ 21

Author(s):

SYRUS KARSAI ◽

CHRISTIAN RAULIN

Keyword(s):

Clinical Practice ◽

Botulinum Neurotoxin ◽

Current Evidence ◽

Botulinum Neurotoxin A

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Botulinum Neurotoxin Serotype A Recognizes Its Protein Receptor SV2 by a Different Mechanism than Botulinum Neurotoxin B Synaptotagmin

Toxins ◽

10.3390/toxins8050154 ◽

2016 ◽

Vol 8 (5) ◽

pp. 154 ◽

Cited By ~ 19

Author(s):

Jasmin Weisemann ◽

Daniel Stern ◽

Stefan Mahrhold ◽

Brigitte Dorner ◽

Andreas Rummel

Keyword(s):

Botulinum Neurotoxin ◽

Serotype A ◽

Protein Receptor ◽

Botulinum Neurotoxin B ◽

Botulinum Neurotoxin Serotype A

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SV2 Is the Protein Receptor for Botulinum Neurotoxin A

Science ◽

10.1126/science.1123654 ◽

2006 ◽

Vol 312 (5773) ◽

pp. 592-596 ◽

Cited By ~ 501

Author(s):

M. Dong

Keyword(s):

Botulinum Neurotoxin ◽

Botulinum Neurotoxin A ◽

Protein Receptor

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Ca2+–Calmodulin regulates SNARE assembly and spontaneous neurotransmitter release via v-ATPase subunit V0a1

The Journal of Cell Biology ◽

10.1083/jcb.201312109 ◽

2014 ◽

Vol 205 (1) ◽

pp. 21-31 ◽

Cited By ~ 33

Author(s):

Dong Wang ◽

Daniel Epstein ◽

Ossama Khalaf ◽

Sankaranarayanan Srinivasan ◽

W. Ryan Williamson ◽

...

Keyword(s):

Synaptic Vesicles ◽

Neuromuscular Junctions ◽

Snare Complex ◽

Dependent Manner ◽

Spontaneous Release ◽

Attachment Protein ◽

Atpase Subunit ◽

Protein Receptor ◽

Vesicle Exocytosis ◽

Cam Regulation

Most chemical neurotransmission occurs through Ca2+-dependent evoked or spontaneous vesicle exocytosis. In both cases, Ca2+ sensing is thought to occur shortly before exocytosis. In this paper, we provide evidence that the Ca2+ dependence of spontaneous vesicle release may partly result from an earlier requirement of Ca2+ for the assembly of soluble N-ethylmaleimide–sensitive fusion attachment protein receptor (SNARE) complexes. We show that the neuronal vacuolar-type H+-adenosine triphosphatase V0 subunit a1 (V100) can regulate the formation of SNARE complexes in a Ca2+–Calmodulin (CaM)-dependent manner. Ca2+–CaM regulation of V100 is not required for vesicle acidification. Specific disruption of the Ca2+-dependent regulation of V100 by CaM led to a >90% loss of spontaneous release but only had a mild effect on evoked release at Drosophila melanogaster embryo neuromuscular junctions. Our data suggest that Ca2+–CaM regulation of V100 may control SNARE complex assembly for a subset of synaptic vesicles that sustain spontaneous release.

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Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00477.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. H2627-H2635 ◽

Cited By ~ 53

Author(s):

Judy L. Morris ◽

Phillip Jobling ◽

Ian L. Gibbins

Keyword(s):

Botulinum Neurotoxin ◽

Vena Cava ◽

Snare Proteins ◽

Botulinum Neurotoxin A ◽

Low Frequencies ◽

Uterine Arteries ◽

Venae Cavae ◽

Protein Receptor

We examined effects of botulinum neurotoxin A (BoNTA) on sympathetic constrictions of the vena cava and uterine artery from guinea pigs to test the role of soluble NSF attachment protein receptor (SNARE) proteins in release of the cotransmitters norepinephrine (NE) and neuropeptide Y (NPY). Protein extracts of venae cavae and uterine arteries showed partial cleavage of synaptosomal associated protein of 25 kDa (SNAP-25) after treatment in vitro with BoNTA (50–100 nM). The rising phase of isometric contractions of isolated venae cavae to field stimulation at 20 Hz, mediated by NE acting on α-adrenoceptors, was reduced significantly by 100 nM BoNTA. However, sustained sympathetic contractions mediated by NPY were not affected by BoNTA. In uterine arteries, noradrenergic contractions to 1-Hz stimulation were almost abolished by BoNTA, and contractions at 10 Hz were reduced by 50–60%. We conclude that SNARE proteins are involved in exocytosis of NE from synaptic vesicles at low frequencies of stimulation but may not be essential for exocytosis of NPY and NE from large vesicles at high stimulation frequencies.

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Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.5.h2124 ◽

2001 ◽

Vol 281 (5) ◽

pp. H2124-H2132 ◽

Cited By ~ 80

Author(s):

Judy L. Morris ◽

Phillip Jobling ◽

Ian L. Gibbins

Keyword(s):

Botulinum Neurotoxin ◽

Snare Complex ◽

Snare Proteins ◽

Botulinum Neurotoxin A ◽

Uterine Arteries ◽

Synaptic Vesicle Exocytosis ◽

Protein Receptor ◽

Autonomic Neurons ◽

Vesicle Exocytosis

The role of the soluble NSF attachment protein receptor (SNARE) protein complex in release of multiple cotransmitters from autonomic vasodilator neurons was examined in isolated segments of guinea pig uterine arteries treated with botulinum neurotoxin A (BoNTA; 50 nM). Western blotting of protein extracts from uterine arteries demonstrated partial cleavage of synaptosomal-associated protein of 25 kDa (SNAP-25) to a NH2-terminal fragment of ∼24 kDa by BoNTA. BoNTA reduced the amplitude (by 70–80%) of isometric contractions of arteries in response to repeated electrical stimulation of sympathetic axons at 1 or 10 Hz. The amplitude of neurogenic relaxations mediated by neuronal nitric oxide (NO) was not affected by BoNTA, whereas the duration of peptide-mediated neurogenic relaxations to stimulation at 10 Hz was reduced (67% reduction in integrated responses). In contrast, presynaptic cholinergic inhibition of neurogenic relaxations was abolished by BoNTA. These results demonstrate that the SNARE complex has differential involvement in release of cotransmitters from the same autonomic neurons: NO release is not dependant on synaptic vesicle exocytosis, acetylcholine release from small vesicles is highly dependant on the SNARE complex, and neuropeptide release from large vesicles involves SNARE proteins that may interact differently with regulatory factors such as calcium.

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Botulinum Neurotoxin Type A in the Treatment of Facial Seborrhea and Acne: Evidence and a Proposed Mechanism

Toxins ◽

10.3390/toxins13110817 ◽

2021 ◽

Vol 13 (11) ◽

pp. 817

Author(s):

Nark-Kyoung Rho ◽

Young-Chun Gil

Keyword(s):

Botulinum Neurotoxin ◽

Type A ◽

Intradermal Injection ◽

Autonomic Nerve ◽

Current Evidence ◽

Sebaceous Glands ◽

Botulinum Neurotoxin Type A ◽

Botulinum Neurotoxins ◽

Sebum Production ◽

Autonomic Nerve Terminals

Intradermal injection of botulinum neurotoxin is a frequently performed procedure in aesthetic dermatology to improve facial skin tone, texture, fine wrinkles, and enlarged pores. In practice, botulinum neurotoxin type A is also used to reduce skin oiliness of the face. There is increasing evidence that acetylcholine plays specific roles in sebum production, suggesting that botulinum neurotoxin type A may reduce sebum production by interfering with cholinergic transmission between sebaceous glands and autonomic nerve terminals. Botulinum neurotoxins can also inhibit several pathogenetic components of acne development, suggesting that botulinum neurotoxins can be used as a safe and effective treatment modality for acne and other skin disorders related to overactivity of sebaceous glands. This review aims to explore the current evidence behind the treatment of facial seborrhea and acne with botulinum neurotoxin type A.

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