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J Pharmacol Exp Ther. 2019 Jun 17. pii: jpet.119.256560. doi: 10.1124/jpet.119.256560. [Epub ahead of print]


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Instituto Teofilo Hernando.
Instituto Teofilo Hernando


Vesicular monoamine transporter-2 (VMAT2) is expressed in the presynaptic secretory vesicles membrane in brain. Its blockade by tetrabenazine (TBZ) causes depletion of dopamine at striatal basal ganglia; being the mechanism underlying its long-standing use in the treatment of Huntington's disease. In the frame of a project aiming the process of exocytosis from vesicles with partial emptying of their neurotransmitter, we unexpectedly found that TBZ facilitated exocytosis, and thus we pursue to characterize such effect. We used bovine chromaffin cells (BCCs) challenged with repeated pulses of high-K+. Upon repeated K+-pulsing, the exocytotic catecholamine release responses were gradually decaying. However, when cells were exposed to TBZ, responses were mildly augmented and decay rate delayed. Facilitation of exocytosis was not due to Ca2+ entry blockade through voltage-activated calcium channels (VACCs) because in fact, TBZ mildly blocked the whole-cell Ca2+-current. However, TBZ mimicked the facilitatory effects of BayK8644 (L-type-VACCs agonist)-elicited exocytosis, effect blocked by nifedipine (VACCs antagonist). On the basis that TBZ augmented secretory responses to caffeine (but not those of histamine), we monitored its effects on cytosolic Ca2+ elevations ([Ca2+]c) triggered by caffeine or histamine. While the responses to caffeine were augmented twice by TBZ, those of histamine were unaffected; the same happened in rat cortical neurons. Hence, we hypothesize that TBZ facilitatates exocytosis by increasing Ca2+ release through the endoplasmic reticulum ryanodine receptor channel (RyR). Confirming this hypothesis are docking results, showing an interaction of TBZ with RyRs. This is consonant with the existence of a healthy Ca2+-induced-Ca2+ release (CICR) mechanism. SIGNIFICANCE STATEMENT: A novel mechanism of action for tetrabenazine (TBZ), a drug used in the therapy of Huntington's disease, is here described. Such mechanism consists in the facilitation by combining of TBZ with the ryanodine receptor (RyR) of the endoplasmic reticulum thereby increasing Ca2+-induced Ca2+ release (CICR). This novel mechanism should be taken into account when considering the efficacy and/or safety of TBZ in the treatment of chorea associated to HD and other disorders. Additionally, it could of interest in the development of novel medicines to treat these pathological conditions.


Huntington's Disease; SERCA ion transporters; calcium; exocytosis; histamine receptors; molecular modeling; neurotransmitters; ryanodine receptors

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