<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CAML Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>CAML (Calcium Modulator and Cyclophilin Ligand)</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>UNC93B1, TMEM111</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>[UNC93B1](/genes/unc93b1)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~64 kDa</td>
</tr>
<tr>
<td class="label">Transmembrane Domains</td>
<td>12 transmembrane helices</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Endoplasmic reticulum, plasma membrane</td>
</tr>
<tr>
<td class="label">Tissue Expression</td>
<td>Ubiquitous; high in brain, T cells</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Target</td>
</tr>
<tr>
<td class="label">GSK-7974437</td>
<td>CRAC</td>
</tr>
<tr>
<td class="label">RyR modulators</td>
<td>ER calcium</td>
</tr>
<tr>
<td class="label">MCU inhibitors</td>
<td>Mitochondrial Ca</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CAML Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>CAML (Calcium Modulator and Cyclophilin Ligand)</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>UNC93B1, TMEM111</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>[UNC93B1](/genes/unc93b1)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~64 kDa</td>
</tr>
<tr>
<td class="label">Transmembrane Domains</td>
<td>12 transmembrane helices</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Endoplasmic reticulum, plasma membrane</td>
</tr>
<tr>
<td class="label">Tissue Expression</td>
<td>Ubiquitous; high in brain, T cells</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Target</td>
</tr>
<tr>
<td class="label">GSK-7974437</td>
<td>CRAC</td>
</tr>
<tr>
<td class="label">RyR modulators</td>
<td>ER calcium</td>
</tr>
<tr>
<td class="label">MCU inhibitors</td>
<td>Mitochondrial Ca</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
CAML (Calcium Modulator and Cyclophilin Ligand), also known as UNC93B1 (Unc-51 Like Autophagy Activating Kinase 1) or TMEM111, is a transmembrane protein primarily localized to the endoplasmic reticulum (ER) that plays critical roles in calcium homeostasis, store-operated calcium entry (SOCE), and cellular survival pathways. Originally identified as a binding partner for cyclophilin B, CAML has emerged as an important regulator of calcium signaling in neurons and glial cells, with implications for multiple neurodegenerative diseases. This page provides comprehensive information about CAML's structure, molecular functions, and role in neurodegeneration.
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CAML is a polytopic transmembrane protein with the following key features:
CAML performs several critical biochemical functions:
CAML is expressed throughout the nervous system:
CAML has been directly implicated in ALS pathogenesis:
Motor Neuron Degeneration: CAML deficiency enhances excitotoxicity-induced motor neuron death. Motor neurons from CAML-deficient mice show increased vulnerability to glutamate toxicity, a key mechanism in ALS pathogenesis[@wang2018].
ER Calcium Depletion: ALS is associated with ER calcium depletion. CAML dysfunction exacerbates this pathology, leading to activation of apoptotic pathways[@anderson2019].
Mitochondrial Calcium Dysregulation: CAML deficiency leads to impaired mitochondrial calcium handling, contributing to mitochondrial dysfunction observed in ALS.
Therapeutic Potential: Enhancing CAML function or restoring store-operated calcium entry may provide neuroprotective benefits in ALS.
CAML intersects with multiple Alzheimer's disease mechanisms:
Calcium Dysregulation: Alzheimer's disease is associated with widespread calcium dysregulation. CAML-regulated store-operated calcium entry is impaired in Alzheimer's disease models[@garcia2018].
Amyloid Toxicity: Amyloid-beta (Aβ) oligomers alter calcium homeostasis through effects on CAML and related pathways. Restoring CAML function may protect against Aβ-induced calcium dysregulation.
ER Stress: CAML function is linked to ER calcium homeostasis. Alzheimer's disease-associated ER stress may be exacerbated by CAML dysfunction.
Synaptic Dysfunction: Calcium dysregulation through CAML contributes to synaptic failure, an early hallmark of Alzheimer's disease.
Dopaminergic Neuron Vulnerability: CAML is expressed in dopaminergic neurons of the substantia nigra. Store-operated calcium entry is particularly important in these pacemaking neurons, which show selective vulnerability in Parkinson's disease[@liu2017].
Mitochondrial Dysfunction: CAML regulates mitochondrial calcium uptake and release. Dysfunction contributes to mitochondrial defects in dopaminergic neurons.
Alpha-Synuclein Toxicity: Calcium dysregulation synergizes with alpha-synuclein aggregation to accelerate dopaminergic neuron loss.
Locus Coeruleus Noradrenergic System: CAML is expressed in noradrenergic neurons of the locus coeruleus, which are also affected in Parkinson's disease.
Oligodendrocyte Death: CAML regulates oligodendrocyte survival. Dysfunction contributes to demyelination in multiple sclerosis models.
Axonal Degeneration: Calcium dysregulation through CAML contributes to axonal degeneration in demyelinating conditions.
Neuroinflammation: CAML modulates microglial activation states that contribute to demyelinating pathology.
Several existing drugs target CAML-related pathways:
UNC93B1 Mutations: Loss-of-function mutations in UNC93B1 cause a spectrum of neurodevelopmental disorders:
The store-operated calcium entry pathway is the primary mechanism through which CAML exerts its effects on neuronal function. This pathway is activated when intracellular calcium stores in the endoplasmic reticulum become depleted, triggering a cascade of events that ultimately lead to calcium influx from the extracellular space through plasma membrane channels.
Step 1: ER Calcium Depletion Detection
When ER calcium stores fall below a threshold level (~40% of resting concentration), the calcium sensor protein STIM1 undergoes a conformational change that exposes its EF-hand domain. This triggers STIM1 oligomerization and translocation to ER-plasma membrane junctions.
Step 2: CAML-Mediated Channel Activation
At these junctional sites, STIM1 interacts directly with CAML, which serves as a critical intermediary. CAML appears to regulate the coupling between STIM1 and the plasma membrane calcium channels, specifically the ORAI family of channels. Without CAML, this coupling is inefficient, leading to reduced calcium influx.
Step 3: Calcium Influx
Activated ORAI1 channels (also known as CRAC - calcium release-activated calcium channels) allow the passage of calcium ions from the extracellular space into the cytoplasm. The resulting calcium influx serves multiple signaling purposes within the neuron.
Step 4: Signal Termination
Calcium influx is terminated through negative feedback mechanisms. High cytoplasmic calcium promotes STIM1 deoligomerization and return to its resting state, closing the CRAC channels.
The endoplasmic reticulum is a critical organelle for protein folding, calcium storage, and lipid metabolism. Disruption of ER homeostasis triggers the unfolded protein response (UPR), which can lead to cell death if not resolved.
CAML and ER Calcium
ER calcium is essential for the function of calcium-dependent chaperones, including calreticulin and calnexin. These chaperones require calcium for their proper folding function. When ER calcium is depleted through CAML dysfunction, protein folding is impaired, triggering the UPR.
CAML and Protein Quality Control
The CAML-cyclophilin B interaction may be involved in protein quality control within the ER. Cyclophilin B has peptidyl-prolyl isomerase activity that accelerates protein folding. The CAML-cyclophilin complex may regulate this process.
CAML in Apoptosis
ER calcium depletion beyond a certain threshold triggers apoptosis through both intrinsic and extrinsic pathways. Mitochondrial calcium overload leads to mitochondrial permeability transition and release of cytochrome c. CAML protects against this process by maintaining ER calcium stores and regulating calcium transfer to mitochondria.
Mitochondria and ER form critical contacts for calcium signaling and metabolic coupling. CAML regulates this inter-organelle communication.
Mitochondrial Calcium Uptake
The mitochondrial calcium uniporter (MCU) complex takes up calcium from the cytoplasm when local calcium concentrations rise during store-operated calcium entry. This calcium uptake stimulates mitochondrial metabolism, supporting ATP production during periods of high demand.
Mitochondrial Dynamics
Calcium signaling through CAML regulates mitochondrial fission and fusion. Excessive calcium leads to excessive fission and fragmentation, contributing to mitochondrial dysfunction.
Bioenergetic Support
Calcium entering through SOCE stimulates pyruvate dehydrogenase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase, increasing NADH and FADH2 production for oxidative phosphorylation.
CAML is highly conserved across species, reflecting its essential functions:
The CAML-STIM-ORAI pathway represents an evolutionarily ancient calcium regulatory system:
Several classes of drugs target store-operated calcium entry:
CRAC Channel Inhibitors
Patient-derived induced pluripotent stem cells (iPSCs) have provided important insights: