Reserpine Irreversibly Inhibits VMAT2, Depletes Neurotransmitters
“this molecule operates pharmacologically as an irreversible inhibitor of the vesicular monoamine transporter 2 (VMAT2). By irreversibly binding to VMAT2 on the membranes of biogenic amine storage vesicles, reserpine disrupts the vesicular packaging of critical neurotransmitters—namely dopamine, norepinephrine, and serotonin—leading to their exposure to cytosolic degradation and subsequent depletion across the central and peripheral nervous systems.”
Summary
Reserpine irreversibly binds to both VMAT1 and VMAT2, blocking the vesicular uptake of dopamine, norepinephrine, and serotonin. This inhibition prevents monoamine storage, exposing them to cytosolic degradation and causing widespread depletion in central and peripheral nervous systems.
Sources 60 searched
- Reserpine-induced Reduction in Norepinephrine Transporter Function Requires Catecholamine Storage Vesicles - PMC
(2002) demonstrated that dopamine uptake via the DAT is diminished following reserpine treatment of rats and following reserpine exposure of cultured cells expressing the DAT. Dopamine uptake is unaffected by reserpine in tissues from transgenic mice lacking VMAT2, suggesting a connection between ...
- The role of the vesicular monoamine transporter 2 in the inhibitory effect of tetrabenazine and valbenazine compared to reserpine on the vesicular release of monoamine transmitters - PMC
Vesicular monoamine transporter 2 (VMAT-2) plays a vital role in packaging cytosolic monoamine transmitters into axon terminal vesicles, which can be released in response to action potentials. Reserpine (RSP), a classical irreversible inhibitor of the monoamine transporter, is an alkaloid used as an antihypertensive drug.
- The vesicular monoamine transporter 2: an underexplored pharmacological target - PMC
The later discovery that reserpine is an irreversible and non-specific VMAT1/2 inhibitor provided a mechanistic explanation for the effects of this compound (5, 6, 91). The anti-hypertensive effect results from VMAT2 inhibition in the sympathetic nervous system and chromaffin cells, reducing ...
- Vesicular Monoamine Transporter 2 - an overview | ScienceDirect Topics
Both VMATs are irreversibly inhibited by reserpine, which initially showed clinical promise as an antihypertensive medication. The depressive effects of reserpine led to its more limited use but helped to formulate the original monoamine hypothesis of affective disorders.
- Reserpine - an overview | ScienceDirect Topics
Reserpine inhibits VMAT1 (peripheral) and VMAT2 (central) at the presynaptic membrane, resulting in the depletion of the synaptic pool of monoamines.
- Inhibitory effect of reserpine on dopamine transporter function - ScienceDirect
It is well established that reserpine causes a persistent inhibition of VMAT-2 function. It is believed commonly that this inhibitory effect is selective for the vesicular transporter, and that reserpine is without effect on plasmalemmal dopamine ...
- Transport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines | Cell Research
Of note, VMAT2 co-exists with VMAT1 in the adrenal glands, and its expression is induced by stress, while VMAT1 level remains constant.23 Both VMAT2 and VMAT1 have a similar affinity for serotonin, but VMAT2 exhibits a preference for catecholamines (e.g., DA, NE, epinephrine) with a 3-fold higher affinity, and even more so for histamine with a 30-fold higher affinity. While the competitive inhibitors reserpine (RES) and ketanserin only show a slight preference for VMAT2 over VMAT1, the non-competitive inhibitors tetrabenazine (TBZ) and its derivatives selectively target VMAT2.22
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