Structure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D Dopamine Receptor.

The dopamine D2 receptor (D2R) is known to elicit effects through activating two major signaling pathways mediated by either G proteins (Gi/o) or β-arrestins. However, the specific role of each pathway in physiological or therapeutic activities is not known with certainty. One approach to the dissection of these pathways is through the use of drugs that can selectively modulate one pathway vs.

(-)-Stepholidine is a potent pan-dopamine receptor antagonist of both G protein- and β-arrestin-mediated signaling.

Rationale: (-)-Stepholidine is a tetrahydroberberine alkaloid that is known to interact with dopamine receptors and has also been proposed as a novel antipsychotic agent. Its suggested novelty lies in the fact that it has been proposed to have D1-like receptor agonist and D2-like receptor antagonist properties. Thus, it might be effective in treating both positive and negative (cognition) symptoms of schizophrenia.

Discovery and characterization of a G protein-biased agonist that inhibits β-arrestin recruitment to the D2 dopamine receptor.

A high-throughput screening campaign was conducted to interrogate a 380,000+ small-molecule library for novel D2 dopamine receptor modulators using a calcium mobilization assay. Active agonist compounds from the primary screen were examined for orthogonal D2 dopamine receptor signaling activities including cAMP modulation and β-arrestin recruitment. Although the majority of the subsequently confirmed hits activated all signaling pathways tested, several compounds showed a diminished ability to stimulate β-arrestin recruitment.

D1-D2 dopamine receptor synergy promotes calcium signaling via multiple mechanisms.

The D(1) dopamine receptor (D(1)R) has been proposed to form a hetero-oligomer with the D(2) dopamine receptor (D(2)R), which in turn results in a complex that couples to phospholipase C-mediated intracellular calcium release. We have sought to elucidate the pharmacology and mechanism of action of this putative signaling pathway. Dopamine dose-response curves assaying intracellular calcium mobilization in cells heterologously expressing the D(1) and D(2) subtypes, either alone or in combination, and using subtype selective ligands revealed that concurrent stimulation is required for coupling.

Wenckebach periodicity at rest that normalizes with tachycardia in a family with a NKX2.5 mutation.

A family with asymptomatic Wenckebach atrioventricular block (Wenckebach periodicity [WP]) has been followed at the investigators' institution for >4 decades. In contrast to all reported cases of WP (except in top-ranking athletes) family members have WP at rest that promptly converts to regular sinus tachycardia with exercise. They also have mild apical noncompaction that has been quite stable.

DBH -1021C-->T does not modify risk or age at onset in Parkinson's disease.

DBH is a candidate gene in Parkinson's disease (PD) and contains a putative functional polymorphism (-1021C-->T) that has been reported to modify PD susceptibility. We examined -1021C-->T in a sample of 1,244 PD patients and 1,186 unrelated control subjects. There was no significant difference in allele (p = 0.

Evaluation of candidate genes for DYX1 and DYX2 in families with dyslexia.

Dyslexia is a common heterogeneous disorder with a significant genetic component. Multiple studies have replicated the evidence for linkage between variously defined phenotypes of dyslexia and chromosomal regions on 15q21 (DYX1) and 6p22.2 (DYX2).