Neurons are the cells responsible for receiving sensory input, sending motor commands to our muscles, and relaying electrical signals throughout the nervous system. While many elements are involved in this signaling, calcium acts as a versatile messenger within these cells. Its role is multifaceted, participating in processes from the transmission of electrical signals to the activation of genes.
How Calcium Enters and Exits Neurons
The concentration of calcium inside a neuron is kept thousands of times lower than the concentration outside. This steep gradient is maintained by channels and pumps that control when calcium enters and exits. The primary entryways are channels in the neuron’s membrane that open in response to specific triggers, allowing calcium to rush into the cell.
One class of entryway is the voltage-gated calcium channel (VGCC). These channels are sensitive to changes in the electrical charge across the neuron’s membrane. When a neuron fires, an electrical impulse called an action potential causes these VGCCs to open and permit a rapid influx of calcium.
Another pathway for calcium entry is through ligand-gated channels, which open when a molecule like a neurotransmitter binds to them. A well-known example is the NMDA receptor, which allows calcium to enter when it binds the neurotransmitter glutamate and the cell membrane is also electrically stimulated. To restore the low internal concentration, neurons use pumps. The plasma membrane Ca2+-ATPase (PMCA) actively pushes calcium out using energy, while the sodium-calcium exchanger (NCX) expels one calcium ion in exchange for three sodium ions.
Essential Functions Driven by Neuronal Calcium
Brief, localized increases in calcium concentration act as signals that initiate a wide range of cellular activities. One primary function is neurotransmitter release. When an electrical signal reaches the end of a neuron, the influx of calcium through VGCCs triggers synaptic vesicles to fuse with the cell membrane and release their contents into the synapse. This process is the basis of chemical communication between neurons.
Calcium signaling is also a basis for learning and memory through synaptic plasticity, which is the ability of synapses to strengthen or weaken over time. Long-term potentiation (LTP), a strengthening of synapses, and long-term depression (LTD), a weakening, are both dependent on calcium influx through NMDA receptors. The pattern and amount of calcium entering the neuron determine if the connection gets stronger or weaker.
Beyond the synapse, calcium can travel to the neuron’s nucleus to influence gene expression. This process allows neurons to produce new proteins that can alter their structure and function in the long term. These changes can support the growth of new connections, promote cell survival, and encode lasting memories.
Maintaining Calcium Balance Within Neurons
To ensure calcium signals are precise and transient, neurons employ an internal system to manage its concentration. This involves not only the pumps that expel calcium but also buffering it and sequestering it within internal compartments. Inside the neuron’s cytoplasm, calcium-binding proteins like calbindin act like sponges, quickly binding to free calcium ions. This buffering action keeps the overall concentration of free calcium low and confines signals to specific locations.
Neurons also use internal organelles as temporary storage sites. The endoplasmic reticulum (ER) can absorb and hold large amounts of calcium, releasing it when specific signals are received. Mitochondria, the cell’s energy producers, also take up calcium when levels get too high. This process helps shape calcium signals and stimulates mitochondria to produce more energy to power the pumps that expel calcium.
Consequences of Neuronal Calcium Imbalance
When the systems that regulate neuronal calcium fail, the consequences can be damaging. Sustained high levels of calcium are toxic, and uncontrolled influx can lead to calcium overload. This state activates destructive pathways that can damage the neuron and lead to cell death, a phenomenon known as excitotoxicity.
In a stroke, for instance, a lack of oxygen disrupts the pumps that remove calcium. This leads to a sustained increase in intracellular calcium, triggering cell death and contributing to brain damage. The over-activation of NMDA receptors is a primary driver of this toxic influx.
Dysregulation of calcium signaling is also implicated in chronic neurodegenerative diseases. In Alzheimer’s disease, disruptions in calcium homeostasis are linked to synaptic dysfunction and neuronal loss. In epilepsy, abnormal firing can cause excessive calcium entry, contributing to seizures and neuronal damage, while failures in calcium management are a factor in Parkinson’s disease, highlighting the importance of this balance for brain health.