Serotonin Receptor in Patients with Prader Willi Syndrome

HBII-52 snoRNA expression has not been detected in people with Prader-Willi syndrome (Kishore and Stamm 2006a; Cavaille et al. 2000). This raises the question whether these patients also exhibit an imbalance in the serotonin mRNA iso-forms. Therefore, brain samples from patients with Prader-Willi syndrome were analyzed by RT-PCR. By using primers that specifically recognize the five editing sites, the 5-HT2C mRNA isoforms could be compared between Prader-Willi patients and age-matched controls. The experiments indicated a significantly reduced editing in three of the four tested sites when the same brain regions are compared. This suggests a reduced expression of the nonedited pre-mRNA in Prader-Willi patients. However, due to the intrinsic problems with human tissues, the protein composition could not be analyzed. These data support a model where HBII-52 promotes exon inclusion of the nonedited exon Vb (Fig. 21.3b).

Exon Vb encodes the second intracellular loop of the receptor that couples to G proteins. Editing changes the amino acids in this loop and alters the receptor properties. The nonedited version of the receptor shows the highest efficacy towards serotonin. Changing the amino acids through editing generates multiple receptor isoforms with 10- to 100-fold lower efficacy (Wang et al. 2000). These conclusions have been derived from studies performed cell culture. The studies have been recently recapitulated in a knock-in mouse model (Kawahara et al. 2008). Mouse lines were engineered where the wild-type 5-HT2C receptor allele was exchanged with an allele generating only the fully edited receptor version. In the mutant allele all five adenosine residues were replaced by guanine residues, which are similar to the inosine residues generated by editing. The mice harboring the fully edited VGV allele of serotonin receptor 2C showed growth retardation, an increased energy expenditure, and a constitutively activated sympathetic nervous system, as well as hyperphagia (Kawahara et al. 2008). These mice did not express any nonedited INI allele. These findings were confirmed by a second, similar mouse model (Morabito et al. 2010). Together, these data indicate the importance of the physiological balance of 5-HT2C splice variants. Some aspects of the phenotype, such as hyperphagia and growth retardation, correlate with the PWS phenotype (Morabito et al. 2010).

Defeat Drugs and Live Free

Defeat Drugs and Live Free

Being addicted to drugs is a complicated matter condition that's been specified as a disorder that evidences in the obsessional thinking about and utilization of drugs. It's a matter that might continue to get worse and become disastrous and deadly if left untreated.

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