Neuronal calcium homeostasis and dysregulation

Abstract

The calcium ion (Ca(2+)) is the main second messenger that helps to transmit depolarization status and synaptic activity to the biochemical machinery of a neuron. These features make Ca(2+) regulation a critical process in neurons, which have developed extensive and intricate Ca(2+) signaling pathways. High intensity Ca(2+) signaling necessitates high ATP consumption to restore basal (low) intracellular Ca(2+) levels after Ca(2+) influx through plasma membrane receptor and voltage-dependent ion channels. Ca(2+) influx may also lead to increased generation of mitochondrial reactive oxygen species (ROS). Impaired abilities of neurons to maintain cellular energy levels and to suppress ROS may impact Ca(2+) signaling during aging and in neurodegenerative disease processes. This review focuses on mitochondrial and endoplasmic reticulum Ca(2+) homeostasis and how they relate to synaptic Ca(2+) signaling processes, neuronal energy metabolism, and ROS generation. Also, the contribution of altered Ca(2+) signaling to neurodegeneration during aging will be considered. Advances in understanding the molecular regulation of Ca(2+) homeostasis and how it is perturbed in neurological disorders may lead to therapeutic strategies that modulate neuronal Ca(2+) signaling to enhance function and counteract disease processes.

FIG. 1.

Mechansims of mitochondrial Ca²⁺ influx and efflux. Ca²⁺ enters the mitochondria through the Ca²⁺ uniporter (CaUP). Close apposition of ER Ca²⁺ release channels and Ca²⁺ uniporter are likely to result in enhanced mitochondrial Ca²⁺ uptake. Inside the mitochondrial matrix, Ca²⁺ can increase the activity of dehydrogenases of the tricarboxic acid cycle (TCA), leading to enhanced feeding of the electron transport chain (ETC) and increased transfer of protons to the intermembrane space. Mitochondrial Ca²⁺ also activates the F1F0 ATPase to produce more ATP. Ca²⁺ is extruded from the mitochondrial matrix through a sodium-dependent mechanism (sodium calcium exchanger, NCX) and a membrane potential-dependent mechanism (calcium proton exchanger, CHX), as well as the permeability transition pore (mPTP). Note that the molecular identities of CaUP, mitochondrial NCX and CHX are unclear.

FIG. 2.

Model for kinetics of mitochondrial Ca²⁺ flux, metabolism and energy levels. If a kinetic delay is assumed between [Ca²⁺]_i and [Ca²⁺]_mit, then activity of the TCA cycle and oxidative phosphorylation will outlast the increase in [Ca²⁺]_i and cytosolic ATP demand, resulting in slightly higher levels of ATP and NADH at the end of a [Ca²⁺]_i transient. In this model, repeated [Ca²⁺]_i transients with the right frequency can therefore result in higher levels of ATP and NADH.

FIG. 3.

Ca²⁺-induced Ca²⁺ release (CICR). A postsynaptic spine is depicted. In CICR, Ca²⁺ enters the cytosol through channels in the plasma membrane. The increased [Ca²⁺]_i will cause the opening of nearby ryanodine receptors (RyR) in the ER membrane. Additionally, increased [Ca²⁺]_i levels result in increased IP₃ levels through phospholipase C (PLC) activation. Opening of RyRs and IP₃ receptors causes “hotspots” of Ca²⁺]_i that may cause further opening of ER Ca²⁺ channels and also promote mitochondrial Ca²⁺ uptake.

FIG. 4.

ER trafficking and Y-secretase. The ER can extend into synaptic spines. Upon activation of NMDA receptors the ER will retract and undergo fission events. Blockade of α- or Y-secretase prevents NMDA-induced retraction of ER membranes from synaptic spines. This suggests that certain, yet unidentified, single transmembrane-domain ER proteins that normally anchor the ER in the synaptic spine are substrates for α- and Y-secretase.

FIG. 5.

Presenilin as an ER leak channel. In this model, uncleaved presenilin 1 (PS1) acts as a Ca²⁺ leak channel in the ER membrane. PS1 mutations causing familial Alzheimer's disease (FAD) result in a loss of function of the ER leak channel properties of PS1. This results in increased [Ca²⁺]_ER and increased CICR. Increased CICR can lead to [Ca²⁺]_i levels that promote excitotoxicity and neuronal cell death.

FIG. 6.

Presenilin as an IP₃R modulator. In this model, Presenilin 1 (PS1) modulates the gating of the IP₃R in the ER. Wild-type PS1 will slightly prolong the time that the IP₃R is in the open confirmation in situation of CICR. PS1 mutations causing familial Alzheimer's disease (FAD) cause PS1 to “lock” the IP₃R in the open conformation and also increase the flux of Ca²⁺ through the IP₃R, resulting in increased [Ca²⁺]_i in a situation of CICR. Depolarization and CICR also lead to increased activity of auto cleaved PS1 in the γ-secretase complex.