Dopamine and the missing ionotropic receptor in the mammalian brain: a perspective

Dopamine presents a striking postsynaptic paradox: it is stored in synaptic vesicles and released in quantal events, yet every established mammalian dopamine receptor (D1–D5) is a GPCR. Whether—and by what mechanism—dopamine can generate rapid postsynaptic ion flow in the mammalian brain therefore remains unresolved. This Perspective shifts attention from release to the receiving cell and reassesses evidence for fast dopamine-evoked changes in membrane conductance. Although quantal dopamine release can generate relatively rapid D2R–GIRK-mediated postsynaptic currents, this indirect metabotropic mechanism may not account for all reported rapid dopamine-dependent changes in membrane conductance. Electrophysiological studies show millisecond-scale dopaminergic responses and direct dopamine-gated channels in invertebrates, whereas a vertebrate-derived hybrid cell line and chick neurons display rapid dopamine-dependent conductance changes or ion-channel regulation. These findings do not identify a mammalian ionotropic dopamine receptor, but they establish electrophysiological phenomena that remain mechanistically unexplained. A recent preprint presents evidence that the delta-type glutamate receptors GluD1 and GluD2 (previously known as delta1 and delta2 glutamate receptors) may act as dopamine-responsive ion channels tuned by G-protein subunits. Independent studies must now determine whether physiological dopamine concentrations evoke rapid GluD currents in native neurons and whether these currents influence defined dopaminergic circuits in vivo. Other experimentally tractable hypotheses include an unconventional dopamine-gated channel, direct coupling between a dopamine GPCR and an ion channel, and receptor homomers or heteromers with emergent ion-handling properties. Molecular-dynamics simulations showing spontaneous Na+ entry deep into D2R support intrareceptor ion access, but not complete transmembrane permeation. By separating established observations, recent preprint data, and mechanistic speculation, this Perspective defines a testable framework for identifying how dopamine binding is converted into postsynaptic ion flow and for determining whether dopamine can support fast neurotransmission in mammals.