TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca²⁺ and Na⁺ Influx.

ABSTRACT: Airway smooth muscle (ASM) contraction is determined by the increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) caused by its release from the sarcoplasmic reticulum (SR) or by extracellular Ca²⁺ influx. Major channels involved in Ca²⁺ influx in ASM cells are L-type voltage-dependent Ca²⁺ channels (L-VDCCs) and nonselective cation channels (NSCCs). Transient receptor potential vanilloid 4 (TRPV4) is an NSCC recently studied in ASM. Mechanical stimuli, such as contraction, can activate TRPV4. We investigated the possible activation of TRPV4 by histamine (His)- or carbachol (CCh)-induced contraction in guinea pig ASM. In single myocytes, the TRPV4 agonist (GSK101) evoked an increase in [Ca²⁺]_i, characterized by a slow onset and a plateau phase. The TRPV4 antagonist (GSK219) decreased channel activity by 94%, whereas the Ca²⁺-free medium abolished the Ca²⁺ response induced by GSK101. Moreover, GSK101 caused Na⁺ influx in tracheal myocytes. GSK219 reduced the Ca²⁺ peak and the Ca²⁺ plateau triggered by His or CCh. TRPV4 blockade shifted the concentration-response curve relating to His and CCh to the right in tracheal rings and reduced the maximal contraction. Finally, the activation of TRPV4 in single myocytes increased the Ca²⁺ refilling of the SR. We conclude that contraction of ASM cells after stimulation with His or CCh promotes TRPV4 activation, the subsequent influx of Ca²⁺ and Na⁺, and the opening of L-VDCCs. The entry of Ca²⁺ into ASM cells via TRPV4 and L-VDCCs contributes to optimal smooth muscle contraction.

SUBMITTER: Montano LM 

PROVIDER: S-EPMC10976253 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature