Endosomal pH in neuronal signaling and synaptic transmission: role of Na(+)/H(+) exchanger NHE5

Abstract

Neuronal precursor cells extend multiple neurites during development, one of which extends to form an axon whereas others develop into dendrites. Chemical stimulation of N-methyl D-aspartate (NMDA) receptor in fully-differentiated neurons induces projection of dendritic spines, small spikes protruding from dendrites, thereby establishing another layer of polarity within the dendrite. Neuron-enriched Na(+)/H(+) exchanger NHE5 contributes to both neurite growth and dendritic spine formation. In resting neurons and neuro-endocrine cells, neuron-enriched NHE5 is predominantly associated with recycling endosomes where it colocalizes with nerve growth factor (NGF) receptor TrkA. NHE5 potently acidifies the lumen of TrkA-positive recycling endosomes and regulates cell-surface targeting of TrkA, whereas chemical stimulation of NMDA receptors rapidly recruits NHE5 to dendritic spines, alkalinizes dendrites and down-regulates the dendritic spine formation. Possible roles of NHE5 in neuronal signaling via proton movement in subcellular compartments are discussed.

Keywords: NMDA receptor; Trk receptors; dendritic spines; endocytic recycling; neurites; neurotrophins; protons; signaling endosomes.

Figure 1

Model of endosomal and synaptic functions of NHE5. At steady state, NHE5 is primarily associated with recycling endosomes, where it acts to acidify the lumen of this compartment. Upon activation of NMDA receptors, recycling endosomes containing NHE5 and Trk receptors are mobilized and recruited to active synapses. One possibility is that signaling downstream of NMDA receptors acutely stimulates NHE5 activity in the endosomal membrane, driving endosomal acidification and promoting endosomal recycling. Following insertion, NHE5 is active on plasma membrane, acting to supress further NMDA receptor activity through localized acidification of the synaptic cleft. In addition, active NHE5 can support the surface expression of Trk receptors and enhance AKT signaling from recycling endosomes. These coordinated activities may help the synapse transition from an initiation phase of LTP into a consolidation phase, limiting excitotoxicity from sustained NMDA receptor activation while promoting synapse strengthening through local neurotrophin signaling.