The Complex Interplay between Toxic Hallmark Proteins, Calmodulin-Binding Proteins, Ion Channels, and Receptors Involved in Calcium Dyshomeostasis in Neurodegeneration

Abstract

Calcium dyshomeostasis is an early critical event in neurodegeneration as exemplified by Alzheimer's (AD), Huntington's (HD) and Parkinson's (PD) diseases. Neuronal calcium homeostasis is maintained by a diversity of ion channels, buffers, calcium-binding protein effectors, and intracellular storage in the endoplasmic reticulum, mitochondria, and lysosomes. The function of these components and compartments is impacted by the toxic hallmark proteins of AD (amyloid beta and Tau), HD (huntingtin) and PD (alpha-synuclein) as well as by interactions with downstream calcium-binding proteins, especially calmodulin. Each of the toxic hallmark proteins (amyloid beta, Tau, huntingtin, and alpha-synuclein) binds to calmodulin. Multiple channels and receptors involved in calcium homeostasis and dysregulation also bind to and are regulated by calmodulin. The primary goal of this review is to show the complexity of these interactions and how they can impact research and the search for therapies. A secondary goal is to suggest that therapeutic targets downstream from calcium dyshomeostasis may offer greater opportunities for success.

Keywords: Calmodulin Hypothesis; Tau; alpha-synuclein; amyloid beta; calcium dysregulation; calmodulin-binding proteins; huntingtin; ion channels; neurodegeneration.

Figure 1

A summary of calcium-dyshomeostasis-related neurodegenerative events in Alzheimer’s (AD), Huntington’s (HD), and Parkinson’s (PD) diseases. Normal physiological levels of intracellular calcium regulate essential neuronal functions including exocytosis, gene regulation, and other events. Calcium dyshomeostasis is an early event in AD, HD, and PD that is involved in the production of disease-related toxic biomarkers (amyloid beta, Aβ; phosphorylated Tau, pTau; mutant huntingtin protein, mHtt; alpha-synuclein, αSyn). Each of these toxic biomarkers in turn adds to calcium dyshomeostasis by affecting receptor and ion channel function. Events linked to the disruption of calcium levels include neuroinflammation, mitochondrial dysfunction, and others, some of which also feed back to compound dysregulated calcium levels.

Figure 2

A diagrammatic summary of receptors, ion channels, sensors/effectors, and buffering proteins involved in calcium homeostasis and dysregulation and their binding to toxic biomarkers and calmodulin. Calcium influx (green channels) into the cytoplasm occurs across the cell membrane through multiple channels (AMPAR, NMDAR, VGCC, TRPC, and Orai1/2). Cytoplasmic contributions to increased intracellular calcium levels come from the endoplasmic reticulum (ER: IP3R and RYR), mitochondria (NCX, mPTP, and Ca²⁺/H⁺ antiporter) and lysosomes (TPC1,2, TRPML1, and VGCC). Intracellular calcium levels can be reduced by efflux (blue channels) via the cell membrane (NCX and PMCA) or by uptake into the ER (SERCA) and mitochondria (MCU, VDAC). Interactions of calmodulin (CaM) and individually studied toxic proteins (Aβ, Tau, Htt, and αSyn) with receptors and ion channels are indicated. The specific receptor and channel subtypes that interact with them are covered in the main text. The acronyms used in the figure are covered in the main text and listed in the Abbreviations.

Figure 3

A comparison of the fundamental effects of calcium homeostasis versus calcium dyshomeostasis on calcium calmodulin function. At normal physiological levels of calcium, altered levels of the divalent cation can shift calmodulin (CaM) from calcium-free CaM (apoCaM) that binds to calcium-independent calmodulin-binding proteins (CaMBPs) to a calcium-bound CaM (Ca²⁺-CaM) that binds to calcium-dependent CaMBPs. The balance between these events controls normal cellular functions. As described by the Calmodulin Hypothesis, calcium dyshomeostasis in neurodegenerative diseases including Alzheimer’s (AD), Huntington’s (HD), and Parkinson’s (PD) can result in high levels of calcium over-activating Ca²⁺-CaM that in turn drives abnormal activities of calcium-dependent CaMBPs, leading to events including, but not limited to, autophagy, neurotoxicity, and neuroinflammation.