# Extracellular acidity and ATP modulate ion currents in human cumulus cells indicating possible roles as metabolic sensors of the follicular microenvironment

## TL;DR

Human cumulus cells respond to acidity and ATP through specific ion channels, suggesting they act as sensors in the follicular environment.

## Contribution

Identification of ion channel subpopulations in human cumulus cells and their modulation by acidity and ATP.

## Key findings

- Three electrophysiological subpopulations of cumulus cells were identified based on ion currents.
- Extracellular acidity and ATP modulate TRPM5-like and other ion currents in cumulus cells.
- Cumulus cells may function as electrochemical sensors in the follicular microenvironment.

## Abstract

Cumulus cells (CCs), derived from granulosa cells, play a key role in supporting oocyte maturation and development through bidirectional communication. However, their electrophysiological properties in humans are poorly defined. Here, we characterized ionic currents and their modulation in primary human CCs obtained from patients undergoing in vitro fertilization. Whole cell patch‐clamp recordings identified three electrophysiological sub‐populations: CC‐type 1, expressing voltage‐dependent K+ currents supported mainly by potassium voltage‐gated channel subfamily A member 5 (KV1.5, KCNA5); CC‐type 2, predominantly showing a barium‐sensitive cationic current attributable to transient receptor potential cation channel subfamily M member 5 (TRPM5); and CC‐type 3, displaying mainly a noisy and voltage‐dependent K+ current typical of potassium calcium‐activated channel subfamily M alpha 1 (BKCa, KCNMA1). Pharmacological experiments, immunocytochemistry and rt‐PCR confirmed the molecular expression of KCNA5, TRPM5 and KCNMA1. Mild extracellular acidification (pH = 6.2) rapidly and reversibly blocked TRPM5‐like current, both inward and outward. Furthermore, 100 μM ATP induced metabotropic responses, evoking coupled intracellular Ca2+ release and activating TRPM5‐mediated currents, as demonstrated by experiments with patch‐clamp and FURA‐2 calcium imaging. These findings reveal that human CCs integrate extracellular acidity and purinergic signals via distinct ion channels, suggesting a role as electrochemical sensors of the follicular microenvironment.

Extracellular acidity and ATP modify electrophysiological profile in human cumulus cell subpopulations, characterized by differential functional expression of TRPM5‐like, BKCa and KV1.5 currents.