The D1-class receptors are primarily coupled to Gαs/olf proteins and stimulate the activity of adenylyl cyclase (AC), leading to the production of the second messenger cyclic AMP (cAMP) ( Beaulieu et al., 2015). There are five subtypes of DA receptors, D1, D2, D3, D4, and D5, that are classified as D1-class receptors (D1 and D5) or D2-class receptors (D2, D3, and D4) ( Kebabian, 1978 Spano et al., 1978). In both the CNS and kidney, DA is produced locally.
DA receptor antagonists have been developed with the goal of blocking hallucinations and delusions that occur in schizophrenic patients, whereas DA receptor agonists are used to alleviate the motor deficits of Parkinson’s disease ( Felder et al., 1990 Klein et al., 2019 Urs et al., 2014). Several pathological conditions such as Parkinson’s disease, schizophrenia, and addiction are related to dysregulation of the neuronal dopaminergic signaling pathway, while hypertension has been attributed to impaired renal dopaminergic signaling ( Felder et al., 1990 Klein et al., 2019). All known cellular actions of DA are mediated by DA receptors, members of the G protein coupled receptor (GPCR) superfamily. DA also regulates physiological responses in non-CNS tissues such as sodium secretion in the kidney ( Missale et al., 1998).
Editor's evaluationĭopamine (DA) is a major hormone and neurotransmitter that regulates a wide range of physiological responses, including reward-motivated behavior, aversion, cognition, and motor control in the central nervous system (CNS) ( Di Chiara and Imperato, 1988 Salery et al., 2020 Sulzer, 2011). Our data provide further evidence for the role of transporters in regulating subcellular GPCR activity. Together, our data suggest that spatially compartmentalized signaling hubs are previously unappreciated regulatory aspects of D1DR signaling.
Using this strategy, we show that Golgi-localized D1DRs regulate cAMP production and mediate local protein kinase A activation. We also introduce a new approach to selectively interrogate compartmentalized D1DR signaling by inhibiting Gαs coupling using a nanobody-based chemical recruitment system. We further demonstrate that dopamine activates Golgi-D1DR in murine striatal medium spiny neurons, and this activity depends on OCT2 function.
We present evidence that activation of the Golgi pool of D1DR is dependent on organic cation transporter 2 (OCT2), a dopamine transporter, providing an explanation for how the membrane-impermeant dopamine accesses subcellular pools of D1DR. Here, using novel nanobody-based biosensors, we demonstrate for the first time that the dopamine D1 receptor (D1DR), the primary mediator of dopaminergic signaling in the brain and kidney, not only functions on the plasma membrane but becomes activated at the Golgi apparatus in the presence of its ligand. As a membrane-impermeant hormone and neurotransmitter, dopamine is thought to signal by binding and activating dopamine receptors, members of the G protein coupled receptor (GPCR) family, only on the plasma membrane. Dopamine is a key catecholamine in the brain and kidney, where it is involved in a number of physiological functions such as locomotion, cognition, emotion, endocrine regulation, and renal function.
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