biostudies-literatureMontano LMConsejo Nacional de Ciencia y Tecnología, MéxicoDirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México293https://www.ebi.ac.uk/biostudies/studies/S-EPMC10976253biostudies-literatureUnknown17(3)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.Pharmaceuticals (Basel, Switzerland)TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca²⁺ and Na⁺ Influx.PMC10976253IA201322IN200522CBF2023-24-1074IA203924IN220219CF72019-137725Montano LMReyes-Garcia JCasas-Hernandez MFCarbajal-Garcia AArredondo-Zamarripa DfalseTRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca²⁺ and Na⁺ Influx.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.2024-01-01T00:00:00Z2024 Feb2025-04-21T21:28:11.537Z2025-04-05T18:22:06.984ZS-EPMC109762533854307910.3390/ph17030293