Acid-sensing ion channels activation and hypoxia upregulate Homer1a expression

Area of Science:

• Neuroscience
• Molecular Biology
• Pathophysiology

Background:

• Dynamic postsynaptic density (PSD) alterations are implicated in central nervous system disorders like ischemic stroke.
• Homer proteins are scaffolding proteins at the PSD regulating synaptic function.
• Homer1a, an immediate early gene, is induced by various stimuli, but its response to acidosis and hypoxia in cerebral ischemia is unknown.

Purpose of the Study:

• To investigate the effect of acidosis and hypoxia on Homer1a expression during cerebral ischemia.
• To elucidate the signaling pathways involved in acid- and hypoxia-induced Homer1a expression.
• To determine the role of Homer1a in neuronal injury during cerebral ischemia.

Main Methods:

• Cultured cortical neurons and neuro-2a cells were used to study Homer1a expression.
• Middle cerebral artery occlusion (MCAO) rat model was employed to assess Homer1a induction in vivo.
• Small interfering RNA (siRNA) was used to knockdown Homer1a expression.

Main Results:

• Acidosis and hypoxia selectively and rapidly upregulated Homer1a, but not Homer1b/c, in cultured neurons.
• Homer1a expression was induced in the brain cortex of MCAO rats.
• Acid-evoked Homer1a induction involved ERK1/2, Akt, and ASIC1a-mediated calcium influx; hypoxia-induced expression relied on ERK1/2.
• Combined acidosis and hypoxia caused cell injury, which was aggravated by Homer1a knockdown.

Conclusions:

• Homer1a expression is rapidly upregulated by acidosis and hypoxia during cerebral ischemia.
• Homer1a signaling pathways, including ERK1/2, Akt, and ASIC1a, are activated by these stimuli.
• Homer1a may function as an activity-dependent regulator involved in the response to cerebral ischemia and subsequent neuronal injury.