RESUMEN
Leucine-rich repeat kinase 2 (LRRK2) is a key molecule in the pathogenesis of familial and idiopathic Parkinson's disease (PD). We have identified two novel LRRK2-associated proteins, a HECT-type ubiquitin ligase, HERC2, and an adaptor-like protein with six repeated Neuralized domains, NEURL4. LRRK2 binds to NEURL4 and HERC2 via the LRRK2 Ras of complex proteins (ROC) domain and NEURL4, respectively. HERC2 and NEURL4 link LRRK2 to the cellular vesicle transport pathway and Notch signaling, through which the LRRK2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. This process negatively regulates Notch signaling through cis-inhibition by stabilizing Dll1/Dl, which accelerates neural stem cell differentiation and modulates the function and survival of differentiated dopaminergic neurons. These effects are strengthened by the R1441G ROC domain-mutant of LRRK2. These findings suggest that the alteration of Notch signaling in mature neurons is a component of PD etiology linked to LRRK2.
Asunto(s)
Endosomas/metabolismo , Enfermedad de Parkinson/enzimología , Proteínas Serina-Treonina Quinasas/fisiología , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Animales , Proteínas Portadoras/metabolismo , Dopamina/metabolismo , Drosophila , Factores de Intercambio de Guanina Nucleótido/metabolismo , Células HEK293 , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Ubiquitina-Proteína LigasasRESUMEN
Sulfonylureas (SU), commonly used in the treatment of type 2 diabetes mellitus (T2DM), stimulate insulin secretion by inhibiting adenosine triphosphate (ATP)-sensitive K(+) (KATP) channels in pancreatic ß-cells. SU are now known to also activate cyclic adenosine monophosphate (cAMP) sensor Epac2 (cAMP-GEFII) to Rap1 signaling, which promotes insulin secretion. The different effects of various SU on Epac2/Rap1 signaling, as well as KATP channels in different tissues, underlie the diverse pancreatic and extra-pancreatic actions of SU. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00014.x, 2010).
RESUMEN
Epac2, a guanine nucleotide exchange factor for the small guanosine triphosphatase Rap1, is activated by adenosine 3',5'-monophosphate. Fluorescence resonance energy transfer and binding experiments revealed that sulfonylureas, widely used antidiabetic drugs, interact directly with Epac2. Sulfonylureas activated Rap1 specifically through Epac2. Sulfonylurea-stimulated insulin secretion was reduced both in vitro and in vivo in mice lacking Epac2, and the glucose-lowering effect of the sulfonylurea tolbutamide was decreased in these mice. Epac2 thus contributes to the effect of sulfonylureas to promote insulin secretion. Because Epac2 is also required for the action of incretins, gut hormones crucial for potentiating insulin secretion, it may be a promising target for antidiabetic drug development.