Vesicular monoamine transporters (VMATs): From discovery to therapeutic targets

Vesicular monoamine transporters (VMAT) are proteins essential for life. They play central roles in neurotransmission and hormone storage and are targets of neuroactive drugs. This retrospective chronicles the decades-long journey of studying VMAT, from early biochemical explorations to the recent surge of structural information. We delve into the serendipitous discoveries, methodological innovations, and collaborations that enhanced our understanding of monoamine storage and synaptic transmission. Importantly, this narrative highlights that a degree of initial "optimistic ignorance"-a failure to fully appreciate the system's complexity-can, paradoxically, be a driving force in scientific exploration. Our early, naïve assumption about VMAT's abundance, while ultimately an oversimplification, was instrumental in launching the project to identify, purify, and characterize the protein. An unprecedented flood of cryo-EM structures now provides invaluable molecular insights into the molecule's intricate workings, synergistically complementing functional studies and offering the crucial framework needed to mechanistically link structure to its function.