DRD1 signaling enhances recovery after traumatic brain injury via an autophagy dependent pathway.

Abstract Although the neurotransmitter dopamine (DA) plays a crucial pathophysiologic role after traumatic brain injury (TBI), its function and specific underlying mechanisms of action remain unclear. In this study, DA inhibits neural death induced by TBI or stretch injury, which is mediated via the dopamine receptor D1 (DRD1). Our results showed that DRD1 signaling promotes receptor interacting protein kinase 1 (RIPK1) ubiquitination via the E3 ubiquitin ligase Chip and degradation through autophagy. Importantly, in vivo data revealed that DRD1 signaling prevented neuronal death, suppressed neuroinflammation, and restored many TBI-related functional sequelae through an autophagy-dependent mechanism. These data reveal a novel mechanism involving dopamine, and suggest that DRD1 activation positively regulates Chip-mediated ubiquitylation of RIPK1—leading to its autophagic degradation.