Hippocalcin signaling via site-specific translocation in hippocampal neurons

Abstract

Hippocalcin is a Ca2+-binding protein, which belongs to the family of neuronal Ca2+ sensors. It is highly expressed in the hippocampus but molecular mechanisms underlying its action in this part of the brain have not been investigated in detail. To study whether intrinsic neuronal activity could result in hippocalcin-mediated signal transduction we examined spontaneous and action potential (AP)-dependent changes in fluorescence of yellow fluorescent protein-tagged hippocalcin (HPCA-YFP) in transiently transfected hippocampal cultured neurons. In 6–12 DIV neurons HPCA-YFP spontaneously translocated longitudinally to specific sites within diffusionally confined domains of neuronal processes. The translocations to these sites were expressed as fast, reversible increases in HPCA-YFP fluorescence coincided with a decrease in adjacent sites indicating genuine protein translocation. Physiologically relevant neuronal stimulation with short trains of action potentials also resulted in fast, simultaneous, reversible, and [Ca2+]i-dependent translocations of HPCA-YFP to several sites synchronizing hippocalcin signaling in different parts of neuronal processes. The amount of translocated protein increased with the number of action potentials in a train decoding the number of APs into the amount of translocated protein. We conclude that hippocalcin may signal within diffusionally restricted domains of neuronal processes in which it might play a physiological role in Ca2+-dependent local activation of specific molecular targets.

The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function

“…They have been shown to have effects on gene expression and are also involved in traffic of proteins to the plasma membrane Brackmann et al 2005). Hippocalcin has been suggested to be involved as a Ca 2þ sensor in long term depression in hippocampal neurons (Palmer et al 2005) and shows a Ca 2þ /myristoyl switch for translocation within such neurons (Markova et al 2008). It has also been implicated in protection from neuronal apoptosis (Mercer et al 2000;Korhonen et al 2004).…”

Neuronal calcium sensors and synaptic plasticity

“…Hippocampal neurons overexpressing YFP (yellow fluorescent protein)-tagged hippocalcin have recently been used to show that transient site specific translocation of hippocalcin to the plasma membrane can occur under resting conditions and after stimulation that causes calcium entry through voltage-operated calcium channels [9]. These reversible increases in fluorescence were observed in spatially restricted areas (1-5 μm) of dendritic trees and axons.…”

“…These reversible increases in fluorescence were observed in spatially restricted areas (1-5 μm) of dendritic trees and axons. Translocation of hippocalcin to the plasma membrane decreased when the extracellular calcium concentration was reduced and was blocked when glutamate was mutated to glutamine, to prevent calcium binding, in EF hands 2 and 3 [9]. Hippocalcin has been shown to play important roles in modulating spatial and associative memory [10] and gating calcium activation of the slow afterhyperpolarization [11].…”

Chronic cocaine disrupts mesocortical learning mechanisms

“…Cytoplasmic rises in calcium either via calcium influx through voltage-gated calcium channels or calcium release from intra-cellular stores binds with proteins of the neuronal calcium sensor (NCS) family, such as hippocalcin and neurocalcin δ (Markova et al, 2008; Tzingounis et al, 2007; Villalobos and Andrade, 2010). Upon binding to calcium, these calcium sensors translocate to the plasma membrane, where they are thought to localize to the K + channels underlying the sAHP (Andrade et al, 2012; Markova et al, 2008).…”