The Lysine mutant is located in the tail
The Lysine429 mutant is located in the tail region of 5-HT2A, which is predicted to be unstructured. This region has been shown to interact, in vitro, with PSD95 and leads to differences in signaling (Xia et al., 2003). The ASK motif, a component of the tail region, is also important for regulation of the receptor in the human isoform and underscores the necessity for studying the tail region in greater detail (Bhattacharya et al., 2010). Since this residue is predicted to lie within a region of ‘high cAMP-cGMP phosphorylation’, studying these second messenger pathways in the context of 5-HT2A signaling could provide useful information about other signaling pathways.
In recent years, the picture of signaling via 5-HT2A has also become increasingly complex. This receptor hetero-dimerizes with a number of receptors such as mGluRs, D2R, CB1R etc. (Lukasiewicz et al., 2010, Moreno et al., 2011, Moreno et al., 2016, Gaitonde and González-Maeso, 2017). It also displays functional selectivity with respect to Pregnenolone Carbonitrile (Strachan et al., 2010, Raote et al., 2013).
We would like to suggest that the property of DA to activate 5-HT2A may also play an important role in the L-DOPA treatment of Parkinson\'s disease patients. Drugs targeting the 5-HT system have been suggested as palliative treatment for L-DOPA induced dyskinesia (LID) and clinically used for Parkinson\'s disease psychosis (Bezard et al., 2013, Stahl, 2016). Previous work has also shown dysregulated release of DA from serotonergic terminals in Parkinson\'s disease rodent models (Carta et al., 2010). From our results it is possible to suggest that post-synaptic 5-HT2A receptors could get activated by DA released by serotonergic terminals. Signaling via these DA-activated 5-HT2A receptors could, therefore, play a role in some of the side-effects of L-DOPA treatment. Our data suggest that of the three mutants of the human 5-HT2A that we have studied, S291A does not have any effect on the phenotypes examined. The other two mutants; T307A and K429A exhibit differences in the phenotypes studied compared to the wild-type receptor. These differences are specific to DA. The effects of these two mutations would only be likely observed in case of dysregulated DA release, particularly from serotonergic terminals. This would most likely be seen in PD patients who have been prescribed L-DOPA, where one could envision DA activating 5-HT2A in vivo, and may contribute to some of the effects of L-DOPA. Since the phenotypes associated with T307A and K429A show hampered signaling on activation of 5-HT2A by DA, we predict that the T307A mutant, reported to be present in the population (Gnomad), could possibly show less side effects due to L-DOPA (Lek et al., 2016). This would require monitoring carriers of this mutation who are also affected by PD.
Other studies have pointed out that in vitro DA can activate other receptor subtypes of the rat and human serotonin receptor family; namely, 5-HT1A, 5-HT2C, 5-HT3 (Woodward et al., 1992, Oz et al., 2003). In this context, it may be fruitful to examine the interactions of dopamine with the 5-HT receptor family in greater detail.
Author contributions SS conceptualized, planned and performed all the experiments, did the analysis and wrote the manuscript. AB contributed to experimental design. MMP conceptualized the project and wrote the manuscript and provided funding.
Introduction Nearly 60 years since it was first demonstrated to be a neurotransmitter (Carlsson et al., 1957), dopamine (DA) is now known to be critical for numerous functions like motor behavior, reward, cognition, metabolism and hormonal secretion (Beaulieu and Gainetdinov, 2011). Dysfunction of the DA system has been implicated in various disorders, including Parkinson\'s disease, attention deficit/hyperactivity disorder (ADHD), schizophrenia and addiction (Albin et al., 1989; Laruelle, 1998; Snyder, 1976; Volkow et al., 2007, 2009). DA is synthesized by tyrosine hydroxylase-containing dopaminergic neurons in various areas of the brain, including key areas such as the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), as well as in the locus coeruleus, hypothalamus and periaqueductal gray (Yetnikoff et al., 2014). Despite relatively small numbers of DA neurons in these areas, their axonal projections are numerous and widespread throughout the brain (Trudeau et al., 2014). Of those, DA neurons from the SNc send their densest projection to dorsal striatal regions, while the VTA preferentially targets the ventral striatum, including the nucleus accumbens (NAc)(Morales and Margolis, 2017; Trudeau et al., 2014).