HomeENGLISH MAGAZINERegulators of G signaling (RGS): the target proteins of the future antidepressant...

Regulators of G signaling (RGS): the target proteins of the future antidepressant pharmacology

Women experience higher rates of depression than men, but the cause of this difference is unknown, which makes their disease sometimes more complicated to treat. The system of female hormones (estrogen) was originally brought up and the fact that female depression is more likely to appear after menopause, when they decrease significantly. But even this hypothesis does not fully explain the individual roots and variability. Although antidepressant medications are very commonly prescribed to treat the condition, sometimes these treatments don’t work for many who use them. The reasons may be several, including the fact that scientists have also identified forms of depression that are not dependent on dopamine and serotonin chemistry at all, which makes drugs like citalopram, sertraline, and fluoxetine entirely ineffective. The brain regions involved in depression can be different and each of them has its own chemistry that characterizes it.

Researchers at the University of California collaborated with scientists from Mt. Sinai Hospital, Princeton University and Laval University, to try to understand how a specific part of the brain, the nucleus accumbens, is affected during depression. The nucleus accumbens is an important region for motivation, response to rewarding experiences and social interactions; all phenomena negatively conditioned by depression. Previous analyzes within the nucleus accumbens showed that different genes were turned on or off in women, but not in men diagnosed with depression. These changes could have caused symptoms of depression or, alternatively, the experience of being depressed could have changed the brain. To differentiate these possibilities, the researchers studied mice that had experienced negative social interactions, inducing stronger depression-related behavior in females than males.

In the rodent model used in this study, negative social interactions changed gene expression patterns in female mice that mirrored patterns seen in women with depression, which is well known to be much more prevalent in women than men. After identifying similar molecular changes in the brains of mice and humans, the researchers chose a gene, regulator of protein G signaling-2 (RGS-2) to manipulate. This gene produces a protein that regulates neurotransmitter receptors that are targeted by antidepressant drugs such as Prozac and Zoloft. RGS comprise a family of proteins that act as highly effective “deactivation switches” of receptor-dependent cell signaling. RGS proteins have recently attracted a lot of attention as a member of this family, RGS4, is considered a candidate marker of vulnerability for schizophrenia and may also play a role in bipolar disorder and Alzheimer’s disease.

It is not new the knowloedge that RGS2 is involved in the neurochemistry of anxious and depressive phenomena: a few years ago it was seen that mice without the brain RGS2 gene responded to the administration of nicotine with an anxiolytic effect, which does not happen in normal mice. In contrast, nicotine in normal mice has an antidepressant effect at low doses, while in mice without the RGS2 gene it takes high doses; this suggests that its genetic deletion reduced sensitivity to the antidepressant-like effects of nicotine. In humans, less stable versions of the RGS2 protein are associated with an increased risk of depression, so the researchers were curious to see if the increase in RGS2 in the nucleus accumbens could reduce depression-related behaviors. When UC researchers increased the RGS2 protein in the nucleus accumbens of the mice, they effectively reversed the effects of stress on these female mice.

They noted that the social approach and preferences for favorite foods increased to the levels observed in female rats that did not experience any stress. This finding highlights a molecular mechanism that contributes to the lack of motivation often observed in depressed patients. For women this may finally have a real connection to their estrogen hormone system. Scientists have known for some years that female mice without ovaries show increased expression of RGS2 in the uterus. When these animals are given estradiol and progesterone, the expression levels of RGS2 are significantly reduced. There is still no data that the same phenomenon can occur in brain cells, both animal and human. But the reduced function of proteins like RGS2 can contribute to difficult-to-treat symptoms in those struggling with mental illness, such as chronic or resistant forms of depression.

If this phenomenon could be confirmed, it would define certain aspects of why depression occurs more often in women and, among them, especially those who are in menopause. Other functions of RGS proteins in the brain include the regulation of neuron differentiation and synaptic plasticity. And depression is partly regarded as a form of impaired functional plasticity of brain cells. There are already a couple of compounds capable of affecting their function. For example, scientists use CCG-50014 in the laboratory as an inhibitor of RGS-4 to study the neuronal response to various stimuli by neurotransmitters, especially in the context of disorders such as schizophrenia and autistic disorder. Another RGS4 inhibitor, CCG-63802, was found to improve opioid receptor-mediated analgesic signaling pathways and reduce chronic neuropathic pain. RGS proteins are therefore deemed to be potential new drug targets to be explored for neuropsychiatric diseases.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Williams AV et al. Biol Psychiatry 2022 Jul 3 in press.

D’Souza MS et al. Biochem Behav. 2022; 213:173338.

Zhu C, Hui L et al. Brain Res. 2020 Nov; 1746:147018.

Rorabaugh BR et al. Eur J Neurosci 2018; 48(5):2110.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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