Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

Abstract

Botulinum toxins can effectively and selectively disrupt and modulate neurotransmission in striated muscle. Recently, urologists have become interested in the use of these toxins in patients with detrusor overactivity and other urological disorders. In both striated and smooth muscle, botulinum toxin A (BTX-A) is internalized by presynaptic neurons after binding to an extracellular receptor (ganglioside and presumably synaptic vesicle protein 2C). In the neuronal cytosol, BTX-A disrupts fusion of the acetylcholine-containing vesicle with the neuronal wall by cleaving the SNAP-25 protein in the synaptic fusion complex. The net effect is selective paralysis of the low-grade contractions of the unstable detrusor, while still allowing high-grade contraction that initiates micturition. Additionally, BTX-A seems to have effects on afferent nerve activity by modulating the release of ATP in the urothelium, blocking the release of substance P, calcitonin gene-related peptide and glutamate from afferent nerves, and reducing levels of nerve growth factor. These effects on sensory feedback loops might not only help to explain the mechanism of BTX-A in relieving symptoms of overactive bladder, but also suggest a potential role for BTX-A in the relief of hyperalgesia associated with lower urinary tract disorders.

Conflict of interest statement

Competing interests

The authors have declared associations with the following company/organization: Allergan, Inc. See the article online for full details of the relationships.

Figures

Figure 1

Structure of BTX-A. (A) 3D crystalline structure of BTX-A. (B) Alternative 3D structural view of BTX-A. The light chain is shown in blue. The remainder of the molecule forms the heavy chain, its C-terminus shown in orange and its N-terminus shown in green. Abbreviation: BTX-A, botulinum toxin A. Permission obtained from Bentham Science Publishers © Aoki KR et al. (2004) Curr Med Chem 11: 3085–3092 (part A) and from Annual Reviews © Simpson LL (2004) Annu Rev Pharmacol Toxicol 44: 167–193 (part B).

Figure 2

Internalization and translocation of BTX-A. (A) BTX-A binds to specific receptors on the neuronal surface via the heavy chain C-terminal binding domain, and enters the neuron by endocytosis. Once within the vesicle, BTX-A undergoes a pH-dependent conformational change that results in dissociation of the light and heavy chains. The catalytic light chain is translocated to the neuron’s cytosol through pores that are formed by the heavy chain N-terminal translocation domain. (B) The BTX-A heavy chain undergoes various conformational changes upon acidification of the vesicle interior, which allows the formation of pores through which the light chain can pass into the cytosol. Abbreviations: BTX-A, botulinum toxin A; H, heavy chain; L, light chain; R, receptor. Permission obtained from Elsevier © Schiavo G et al. (1990) J Physiol (Paris) 84: 180–187.

Figure 3

Inhibition of acetylcholine exocytosis by BTX-A. (A,B) Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex that allows the membrane of the acetylcholine-containing synaptic vesicle to fuse with the neuronal cell membrane. The synaptic fusion complex is a set of SNARE proteins, which includes synaptobrevin, SNAP-25 and syntaxin. (C) After membrane fusion, acetylcholine is released into the synaptic cleft and then bound by receptors on the muscle cell. (D) BTX-A binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocytosis. (E,F) The light chain of BTX-A cleaves specific sites on the SNAP-25 protein, preventing complete assembly of the synaptic fusion complex and thereby blocking acetylcholine release. Without acetylcholine release, the muscle is unable to contract. Abbreviations: BTX-A, botulinum toxin A; SNAP-25, synaptosome-associated protein 25 kDa; SNARE, soluble N-ethylmaleimide-sensitive fusion attachment protein receptor. Permission obtained from Elsevier © Smith CP and Chancellor MB (2004) J Urol 171: 2128–2137.