Dopamine

A recent report in Science from Dr. H. Robert Horvitz identifies three novel ligand-gated chloride channel receptors for the biogenic amines serotonin, dopamine and tyramine in c. elegans. While this work does not directly address Parkinson's disease, the discovery of a novel dopamine receptor has the potential to make a large impact on PD research.

The current standard treatment for Parkinson's disease involves the use of dopamine based therapies to increase dopaminergic transmission in order to counteract pathological dopamine depletion. However, while currently prescribed dopamine agonists (ropinerole, apomorphine, and pramipexole) may yield fewer motor side effects, they are not as effective as L-DOPA in providing symptomatic relief (Rascol et al., 2000; Parkinson Study Group, 2000). The underlying cause of this discrepancy remains unclear - could there be other receptors, in addition to D1 and D2 receptors, that are activated by L-DOPA and contribute to dopaminergic control of motor function?

The identification of a novel class of dopamine receptor in c. elegans may help illuminate this mystery. Known dopamine receptors in the mammalian brain (including D1 and D2 receptors) are G-protein coupled receptors (GPCRs). Ringstad et al. characterize a ligand-gated chloride channel (LGC-53) found in c. elegans that has a high affinity for dopamine and is blocked by currently prescribed dopamine antagonists haloperidol, spiperone, and risperidone. Additionally, while no motor deficits were observed in lgc-53 deletion mutants, the tyramine receptor lgc-55 deletion mutant did demonstrate behavioral deficits, confirming a physiological role for the receptor.

This work does raise some interesting questions for future study:

• It is unknown whether these receptors also exist in the mammalian nervous system and if so, what roles they play. If these novel receptors are conserved, more complex biological systems may reveal other behavioral deficits unobserved in the worm.
• The mechanistic differences between the slower transmission of GPCRs versus the rapid signaling sent by ligand-gated ion channels may provide additional clues to discrete functions.
• The authors do not present data on whether the receptor is activated by dopamine agonists, though this question may shine light on the differences between the effects of dopamine agonists and L-DOPA on the human brain.

Ringstad N, Abe N, and Horvitz HR. Ligand-Gated Chloride Channels Are Receptors for Biogenic Amines in C. elegans. Science (2009) 325: 96-100.

This week in The Journal of Neuroscience, Almeida et al. report that cAMP-mediated induction of neuronal CREB-dependent gene transcription by D1 dopamine receptor (DAR) activation requires Ca²⁺ entry through NR2B-containing NMDA receptors (NMDARs). Surprisingly, NMDAR activation is accomplished by L-aspartate (but not glutamate), release of which is induced by cAMP. Although this novel signaling pathway was characterized in immature cortical neurons in vitro, this autocrine or paracrine signaling mechanism may continue to operate in mature neuronal networks throughout the brain, including in the striatal neurons that are the targets of the dopaminergic neurons that degenerate in PD. This study indicates that dopaminergic regulation of neuronal function may be more complicated than previously thought, with aspartate-mediated NMDAR activation joining direct effector phosphorylation by PKA, mediation by DARPP-32, and physical association of DARs with NMDARs as potential mechanisms of action. Moreover, these findings suggest additional potential pharmacological targets for treatment of PD.

Luis E. F. Almeida, Peter D. Murray, H. Ronald Zielke, Clinton D. Roby, Tami J. Kingsbury and Bruce K. Krueger. Autocrine activation of neuronal NMDA receptors by aspartate mediates dopamine- and cAMP-induced CREB-dependent gene transcription. Journal of Neuroscience 29(40):12702–12710 (2009)