Intestinal cells glowing with electrical activity, influenced by an ATP molecule

Gut Check: How ATP Affects Your Intestines' Pacemaker Cells

Mira Elwood in Health & Wellness December 2025 • 4 min read.

"New research reveals how adenosine triphosphate (ATP) influences the interstitial cells of Cajal (ICCs), potentially paving the way for novel treatments for gastrointestinal motility disorders."

The gastrointestinal (GI) tract relies on precise muscle contractions to move food along, a process heavily influenced by electrical signals known as slow waves. These slow waves determine the frequency and timing of GI muscle contractions, playing a pivotal role in overall digestive motility. But what controls these slow waves? The answer lies within specialized cells called interstitial cells of Cajal, or ICCs.

ICCs act as the gut's natural pacemakers. They generate spontaneous electrical currents that spread to surrounding smooth muscle cells, coordinating their contractions. Think of them as the conductors of a finely tuned orchestra, ensuring everything moves in harmony. Disruptions to the ICC network can lead to various motility disorders, highlighting their importance in maintaining a healthy digestive system.

Adenosine triphosphate, better known as ATP, is not just an energy source within cells; it also acts as a signaling molecule outside of cells. It communicates with cells via purinergic receptors. These receptors are abundant in the GI tract and play a key role in modulating motility, secretion, and absorption. New research is shedding light on how ATP interacts with ICCs, offering potential insights into new treatments for digestive disorders.

How Does ATP Influence Pacemaker Activity in Intestinal Cells?

Intestinal cells glowing with electrical activity, influenced by an ATP molecule

A recent study investigated how external ATP affects the pacemaker activity of ICCs in the small intestines of mice. The researchers used advanced techniques, including whole-cell patch clamp and intracellular calcium imaging, to observe cellular behavior. They found that ATP dose-dependently depolarized the resting membrane of ICCs, meaning it made the cells more electrically active. This depolarization led to the production of tonic inward pacemaker currents, which are essential for initiating muscle contractions.

The effects of ATP were counteracted by suramin, a purinergic P2 receptor antagonist. This indicates that ATP's influence on ICCs is mediated through P2 receptors, a specific class of receptors that bind to ATP. Further experiments revealed that these ATP-induced effects were suppressed when the cells were placed in a sodium-free environment or treated with nonselective cation channel blockers like flufenamic acid and niflumic acid.

Sodium's Role: Removing external sodium ions significantly reduced the ATP-induced pacemaker currents, suggesting that sodium channels are involved in the process.
Calcium's Importance: The removal of external calcium ions or the use of thapsigargin, which inhibits calcium uptake into the endoplasmic reticulum, also diminished the effects of ATP on pacemaker currents. This indicates that calcium influx and release play a crucial role in ATP's modulation of ICC activity.
Increased Calcium Oscillations: External ATP was found to enhance spontaneous calcium oscillations within the ICCs, further supporting the idea that calcium dynamics are central to ATP's mechanism of action.

These findings suggest that external ATP modulates pacemaker activity by activating nonselective cation channels through both external calcium influx and the release of calcium from intracellular stores, specifically the endoplasmic reticulum. By acting on purinergic P2 receptors, ATP can fine-tune GI motility by influencing the electrical behavior of ICCs.

The Bigger Picture: ATP and Future GI Treatments

This research highlights the complex interplay between ATP and ICCs in regulating gastrointestinal motility. By understanding the specific mechanisms through which ATP influences pacemaker activity, scientists can potentially develop targeted therapies for motility disorders. Future research could focus on identifying specific P2 receptor subtypes involved in this process and designing drugs that selectively modulate their activity. This could lead to new treatments for conditions like irritable bowel syndrome (IBS) or chronic constipation, offering relief to millions.

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Everything You Need To Know

What is the role of interstitial cells of Cajal (ICCs) in the gastrointestinal tract?

Interstitial cells of Cajal (ICCs) are the gut's natural pacemakers, responsible for generating spontaneous electrical currents. These currents spread to the surrounding smooth muscle cells, coordinating their contractions. ICCs act as conductors of a finely tuned orchestra, ensuring everything moves in harmony within the gastrointestinal (GI) tract. Disruptions to the ICC network can lead to various motility disorders, highlighting their importance in maintaining a healthy digestive system.

How does ATP influence the pacemaker activity of ICCs?

ATP, acting as a signaling molecule, influences the pacemaker activity of interstitial cells of Cajal (ICCs). Research indicates that external ATP depolarizes the resting membrane of ICCs, making them more electrically active. This depolarization leads to the production of tonic inward pacemaker currents, essential for initiating muscle contractions. This process is mediated through purinergic P2 receptors, as ATP's effects are counteracted by suramin, a P2 receptor antagonist. The effect of ATP on ICCs involves sodium and calcium channels, influencing the electrical behavior of ICCs. External ATP enhances spontaneous calcium oscillations within the ICCs, further supporting the idea that calcium dynamics are central to ATP's mechanism of action.

What are purinergic P2 receptors, and how do they relate to ATP's function in the GI tract?

Purinergic P2 receptors are a specific class of receptors that bind to ATP. These receptors are abundant in the gastrointestinal (GI) tract and play a key role in modulating motility, secretion, and absorption. When ATP interacts with ICCs, it's mediated through P2 receptors. ATP's influence on ICCs is counteracted by suramin, a purinergic P2 receptor antagonist. This indicates that the effect of ATP on ICCs is related to P2 receptors, a specific class of receptors that bind to ATP. By acting on purinergic P2 receptors, ATP can fine-tune GI motility by influencing the electrical behavior of ICCs.

How does the interplay between sodium and calcium affect ATP's influence on ICCs?

Both sodium and calcium play crucial roles in ATP's influence on interstitial cells of Cajal (ICCs). The removal of external sodium ions significantly reduces the ATP-induced pacemaker currents, suggesting that sodium channels are involved in the process. Similarly, removing external calcium ions or inhibiting calcium uptake also diminishes the effects of ATP on pacemaker currents, indicating that calcium influx and release are crucial in ATP's modulation of ICC activity. ATP enhances spontaneous calcium oscillations within the ICCs, supporting the idea that calcium dynamics are central to ATP's mechanism of action. The effect of ATP on ICCs involves sodium and calcium channels, influencing the electrical behavior of ICCs, thus impacting GI motility.

What are the potential implications of this research for future treatments of gastrointestinal motility disorders?

This research highlights the complex interplay between ATP and ICCs in regulating gastrointestinal motility. By understanding the specific mechanisms through which ATP influences pacemaker activity, scientists can potentially develop targeted therapies for motility disorders like irritable bowel syndrome (IBS) or chronic constipation. Future research could focus on identifying specific P2 receptor subtypes involved in this process and designing drugs that selectively modulate their activity. This could lead to new treatments, offering relief to millions suffering from GI disorders. The research suggests that ATP can be a key player in managing digestive health by influencing the electrical activity of ICCs.