Ureshino RP et al. (2019), The Interplay between Ca2+ Signaling Pathways a...

ECB-ART-48767

Int J Mol Sci 2019 Nov 28;2023:. doi: 10.3390/ijms20236004.

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The Interplay between Ca2+ Signaling Pathways and Neurodegeneration.

Ureshino RP , Erustes AG , Bassani TB , Wachilewski P , Guarache GC , Nascimento AC , Costa AJ , Smaili SS , Pereira GJDS .

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Calcium (Ca2+) homeostasis is essential for cell maintenance since this ion participates in many physiological processes. For example, the spatial and temporal organization of Ca2+ signaling in the central nervous system is fundamental for neurotransmission, where local changes in cytosolic Ca2+ concentration are needed to transmit information from neuron to neuron, between neurons and glia, and even regulating local blood flow according to the required activity. However, under pathological conditions, Ca2+ homeostasis is altered, with increased cytoplasmic Ca2+ concentrations leading to the activation of proteases, lipases, and nucleases. This review aimed to highlight the role of Ca2+ signaling in neurodegenerative disease-related apoptosis, where the regulation of intracellular Ca2+ homeostasis depends on coordinated interactions between the endoplasmic reticulum, mitochondria, and lysosomes, as well as specific transport mechanisms. In neurodegenerative diseases, alterations-increased oxidative stress, energy metabolism alterations, and protein aggregation have been identified. The aggregation of α-synuclein, β-amyloid peptide (Aβ), and huntingtin all adversely affect Ca2+ homeostasis. Due to the mounting evidence for the relevance of Ca2+ signaling in neuroprotection, we would focus on the expression and function of Ca2+ signaling-related proteins, in terms of the effects on autophagy regulation and the onset and progression of neurodegenerative diseases.

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Genes referenced: gli3 LOC115919910 LOC593358

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Figure 1. Crosstalk between proteins associated with neurodegenerative diseases and Ca2+ physiology. The cellular Ca2+ homeostasis is regulated by a synchronized system of pumps and channels, located in plasma membranes of cells and organelles. The influx of calcium (Ca2+) from the extracellular space is mediated by voltage-gated Ca2+ channels (VGCC), including L-type, P-type, and N-type channels. Dysfunctions of these channels have been described in Parkinson’s disease (PD), where the A53T mutation in α-synuclein upregulates and hyperactivates N-type channels. In Alzheimer’s disease (AD), β-amyloid peptide (Aβ) stimulates L-type channels, which can be blocked by nimodipine. In prion disease, prion protein (PrPSc) can inhibit the L-type channel while reducing the activity of the N-type channel. The store-operated Ca2+ channel (SOCC) mediates Ca2+ influx in response to reduced intracellular stocks. Mutant huntingtin (mHtt) promotes SOCC hyperactivation, resulting in increased Ca2+ entry through the channel. The Ca2+ level in the endoplasmic reticulum (ER) is controlled by stromal interaction molecule 1 (STIM1), which under low ER Ca2+ concentrations forms dimers and interacts with the ORAI channel, promoting the influx of Ca2+ to the cytosol. Many receptors are bound to G protein complexes (GPCR) activating phospholipase C (PLC) and cyclic adenosine monophosphate (AMPc), promoting the synthesis of inositol-1,4,5-triphosphate (IP3), which upon binding to the inositol-1,4,5-triphosphate receptor (IP3R) in the ER membrane, promotes the release of ER Ca2+ to the cytosol. Increased cytosolic Ca2+ levels also activate the ryanodine receptor (RyR), releasing Ca2+ by a phenomenon called Ca2+-induced Ca2+ release (CICR). In Huntington’s disease, mHtt directly influences IP3R and RyR activities, increasing cytosolic Ca2+ concentrations and decreasing the levels of this ion in the ER. Mutant presenilin, associated with AD, can also modulate the activity of IP3R, increasing the Ca2+ release by this channel. Sarcoendoplasmic reticular Ca2+ ATPase (SERCA) mediates the transport of Ca2+ back to the ER lumen. Contact sites between the ER and mitochondria are called mitochondrial-associated ER membranes (MAM), which also represent a region of intense Ca2+ traffic. IP3R and voltage-dependent anion channel 1 (VDAC1) are the main channels involved in MAM Ca2+ transport. Initially, Ca2+ stored in the ER is released through IP3R, diffuses through the MAM, is taken up by the VDAC, located in the outer mitochondrial membrane (OMM), and transported to the mitochondrial matrix by the mitochondrial Ca2+ uniporter (MCU). The mitochondrial chaperone glucose-related protein 75 (GRP75) physically interacts with both channels and facilitates Ca2+ transport. In PD, it has been proposed that α-synuclein could be inserted in the MAM, but its pathological role has yet to be elucidated. In the mitochondria, the influx of Ca2+ is mediated by VDAC and MUC, as mentioned above, and the efflux is mediated by Ca2+ exchangers, Na+/Ca2+ exchanger (NCLX), and mitochondrial H+/Ca2+ exchanger (mHCX), in the inner mitochondrial membrane (IMM). The controlled opening and closing of the mitochondrial transition pore (mPTP) also mediates the Ca2+ efflux from the mitochondria. However, sustained mPTP opening has been linked to apoptosis. The senile plates and mHtt can affect the mPTP, consequently altering the activity of this pore. In mitochondria, the α-synuclein, Aβ, and Tau can directly impair the complex I activity. Lysosomes are another important organelle directly involved in Ca2+ signaling and homeostasis and express a variety of Ca2+ channels, including transient receptor potential (TRP) and two-pore channels (TPCs). Nicotinic acid adenine dinucleotide phosphate (NAADP) activates TPC, promoting the release of Ca2+ from lysosomes, which is amplified by CICR via RyR activation. In PD, mutations in leucine-rich repeat kinase 2 (LRRK2) leads to the upregulation of the protein and increased Ca2+ release through TPC. The Ca2+/H+ exchanger (CAX) mediates the influx of Ca2+ in lysosomes, and H+-ATPase promotes lysosomal acidification. The red arrows demonstrate the pathological stimulus and influence of each protein in Ca2+ channels and pumps. The black arrows show the physiological paths of cellular Ca2+ homeostasis.

Figure 2. Ca2+ is mostly involved in mTOR-independent autophagy induction. The canonical pathway of regulation and induction of autophagy is controlled by the mammalian/mechanistic target of rapamycin (mTOR). A variety of factors can inhibit mTOR and lead to autophagy activation. Inactivated mTOR activates and phosphorylates Unc-51 like autophagy activating kinase (ULK1) complex, forming a multiprotein complex with Beclin1, VPS34, AMBRA1, VPS34, and PI3K-III, known as the PI3K class III complex, and the formation of PIP3 (phosphatidylinositol 3-phosphate). PIP3 induces the initiation of the phagophore membrane, while the elongation is controlled by the Atg12-Atg5-Atg16L complex. At the same time, LC3 is lipidated and conjugated to phosphatidylethanolamine, forming the LC3-II and participating in the cargo recognition and closure of the autophagosome membrane. Cargo is degraded by the fusion of autophagosomes and lysosomes and is performed by lysosomal hydrolases. Ca2+ physiology and signaling have an important role in the induction of autophagy. Increased cytosolic Ca2+ levels, mediated by SOCC or release of intracellular stores (induced by thapsigargin, vitamin D ionomycin, or Ru360), can activate Ca2+calmodulin dependent kinase 2 (CaMKK2), which will activate protein kinase B (AKT); or alternatively, Ca2+ can directly activate AKT, initiating the signaling processes necessary for autophagy induction. The Ca2+ released from the lysosome can also activate AKT and CaMKK2, by the stimulating two-pore channels (TPC) and transient receptor potential cation channel, mucolipin subfamily, member 1 (TRPML1). In PD, the mutated protein leucine-rich repeat kinase 2 (LRRK2) can upregulate TPC activity, causing increased Ca2+ transport through the channel, and augment autophagy. The stored lysosomal Ca2+ released via TRPML1 activates calcineurin, which leads to transcription factor EB (TFEB) dephosphorylation. Dephosphorylated TFEB translocates to the nucleus, regulating lysosomal genesis, activation of autophagy, and increasing cell clearance. On the other hand, reduced Ca2+ channel activity can attenuate the autophagic response. Knocking-out presenilin leads to reduced lysosomal H+-ATPase pump and SERCA activities, as well as reduced autophagy. SERCA inhibition with thapsigargin shows similar results. Attenuated IP3R activity inhibits Ca2+ release from the ER, consequently reducing the CICR via RyR activation and decreases the autophagic response.

References [+] :

Abeti, Mitochondrial Ca(2+) in neurodegenerative disorders. 2015, Pubmed