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  • With one exception all receptors for

    2024-06-05

    With one exception, all receptors for dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT), and norepinephrine are metabotropic receptors. The five metabotropic DA receptors (D1–D5) in the CNS are involved in motivation, pleasure, cognition, learning, memory, fine motor control, and modulate neuroendocrine signaling. No ionotropic DA receptors exist. Metabotropic serotonin receptors (5-HT) modulate the release of many transmitters and hormones in the CNS; unlike DA, however, serotonin has a unique ionotropic receptor, the ligand-gated ion channel 5-HT. In neocortical structures, 5-HT receptors are expressed on inhibitory GABAergic interneurons where they modulate excitability. 5-HT receptors are also expressed on glutamatergic Cajal–Retzius cells in the cortex and granule cells in the cerebellum . Finally, metabotropic norepinephrine receptors include G-coupled (α) adrenergic receptors that increase intracellular Ca and smooth muscle contraction, and G-coupled (α) adrenergic receptors that inhibit neurotransmitter release. β-Adrenergic receptors are G-coupled (β also couples to G) and increase intracellular cAMP, resulting in enhanced cardiac muscle contraction and smooth muscle relaxation. Similarly to DA, no ionotropic norepinephrine receptors exist. Ionotropic receptors are catalogued for many ligands – but except for the 5-HT receptor, however, none exist for the monoamines. Or do they? Consider the monoamine transporters DAT (DA transporter), SERT (serotonin), and NET (norepinephrine). DAT, for example, has an established role in controlling DA levels in the TCEP and is under intense investigation as a molecular target for amphetamine (AMPH), cocaine, and synthetic cathinones , , , . compares the responses from NMDA, AMPA, and GABAergic ionotropic receptors to those from DAT in response to DA or AMPH. These data suggest that DAT may in effect be viewed as an ionotropic receptor for DA because it generates comparable currents under similar conditions to authentic ionotropic receptors. In addition, drugs such as AMPH generate similar fast-acting currents. Thus, alongside its role as a DA transporter, DAT generates currents comparable to those generated by glutamatergic and GABAergic ionotropic receptors. The presynaptic dopaminergic terminal therefore contains both an inhibitory metabotropic DA receptor (D2) and an excitatory ionotropic DA receptor (DAT). Because DAT contains an endogenous leak current, drugs such as cocaine, which block the leak, are inhibitory. A similar story obtains for serotonin or norepinephrine. DAT, SERT, and NET act as excitatory or inhibitory ionotropic receptors depending on the ligand . For many years, we have referred to the current-generating property of monoamine transporters as electrogenic or channel-like; recognizing monoamine transporters as ligand-modulated ion channels in addition to their traditional role may change this perspective. and data already support glutamate and GABA transporters as ligand-gated ion channels, but this is a controversial concept for monoamine transporters. Perhaps this is because data for monoamine transporters acting as receptors are scarce. Nevertheless, Ingram . showed that DA and AMPH modulate the excitability of mammalian dopaminergic neurons . Carvelli documented DAT currents in dopaminergic neurons , and Bruns compared 5-HT ionotropic receptor currents and 5-HT-induced SERT currents in the leech synapse (). Viewing monoamine transporters as ionotropic receptors, where almost none exist, may stimulate new experiments to test this perspective.
    Introduction In a simple sense, a transporter is a protein that functions to move a substrate from one location to another. Most often, this is to move an ion or molecule across a lipid bilayer membrane barrier, where passive diffusion is minimal or limited by such an ionic or concentration gradient. The majority of transporters are located at epithelial barriers (eg, intestinal epithelia, hepatocytes, brain capillary endothelial cells, choroid plexus cells, kidney proximal tubule cells), but they are also found on intracellular membranes (vesicles, mitochondria, Golgi, vacuoles, endosomes).1, 2 The movement of the substrate can be passive or active, involve cotransport or anti-transport of other molecules or ions (which may involve a second transporter), and may or not require expenditure of energy (hydrolysis of adenosine triphosphate [ATP]). The molecular mechanism of solute transport remains unknown for the majority of transporters, but is in general might be described by an alternating access model, where the substrate binding site is exposed to one side, transits through an occluded state (not exposed to either side of membrane), and then exposed to the opposite side. The determination of the three-dimensional structures of these important proteins, defining the locations of substrate interactions, and delineating the mechanism of substrate movement are active areas of research as transporters are involved in many aspects of human health and disease. Mutations and variations in transporter genes are the basis of several inherited diseases, and an astonishing number of therapeutic drugs currently used in medicine are either substrates for or inhibitors of transporters.4, 5 As examples, inhibitors of the neuronal membrane serotonin transporter (SERT/SLC6A4) such as fluoxetine (Prozac) and citalopram (Celexa) are commonly used in neurology and psychiatry, and inhibitors of the sodium-glucose cotransporter 2 (SGLT2/SLC5A2) as a recent therapy for type 2 diabetes mellitus (eg, Farxiga).