Transient Receptor Potential Cation Channel Subfamily V Member 4 (TRPV4): A Multifunctional Channel and Potential Therapeutic Target for Analgesia

瞬時感受器電位香草酸第四亞型離子通道（Transient Receptor Potential Vanilloid, 4 Subfamily; TRPV 4）一個多功能的離子通道

范洪春(Hueng-Chuen Fan) ； Xuming Zhang ； Peter A. McNaughton

《童綜合醫學雜誌》 11卷2期 (2017/12) Pp. 73-84

摘要

Transient receptor potential cation channel subfamily V member 4 (TRPV4), is a polymodal receptor activated by hypotonicity, innocuous heat, and phorbol esters. TRPV4 is expressed in several tissues, including the lungs, spleen, kidneys, testes, fat, cochleas, skin, smooth muscle, liver, vascular endothelium, central nervous system, and dorsal root ganglia. In addition to this wide distribution, it has a broad spectrum of activators and is a nociceptor in inflammatory hyperalgesia generated by inflammatory mediators in inflamed tissues. After tissue injury, inflammatory mediators activate downstream kinases, specifically protein kinase C (PKC) and protein kinase A (PKA), both of which sensitize TRPV4 through phosphorylation and cause hyperalgesia. Despite intensive efforts to develop pain-blocking therapy based on this pathway, several nonspecific effects and side effects have halted the development of TRPV4 blockers. AKAP79 (A kinase anchoring protein 79) can orchestrate distinct signaling molecules, such as PKA and PKC, and enhance their phosphorylation to modulate target proteins. Interestingly, the administration of small interfering RNA against AKAP79 can abolish inflammatory hyperalgesia and is a promising target for the development of a novel class of analgesics.

關鍵字

Transient Receptor Potential ； Transient Receptor Potential Cation Channel Subfamily V Member 4 ； Protein Kinase A ； Protein Kinase C ； Small Interfering RNA ； A Kinase Anchoring Protein

並列摘要

瞬時感受器電位香草酸第四亞型離子通道蛋白（Transient Receptor Potential Vanilloid, 4 Subfamily; TRPV4）是可被低張力（hypotonicity）、溫熱（innocuous heat）、或者由佛波酯（phorbol esters）等所活化的多型受體（polymodal receptor）。TRPV4 在人體分布廣泛，包括肺、脾臟、腎臟、睪丸、脂肪、耳蝸、皮膚、平滑肌、肝臟、血管內皮、中樞神經系統、以及背根神經元。TRPV4具有多樣的活化物以及廣泛的分布，它亦是發炎性痛覺過敏（inflammatory hyperalgesia）的痛覺接受器。發炎性痛覺過敏是發炎組織內發炎的媒介物（inflammatory mediators）的作用所致。當組織受損後，發炎的媒介物可以活化蛋白激酶C（protein kinase C; PKC）和蛋白激酶A（protein kinase A; PKA）。此兩種激酶在發炎性痛覺過敏（inflammatory hyperalgesia）的過程中扮演關鍵性角色，因為此兩種激酶會磷酸化TRPV1和TRPV4，進而增加這些通道的敏感性，導致發炎性痛覺過敏的疼痛。雖然許多藥廠想要藉著發展TRPV4的阻斷劑來治療疼痛，但因為阻斷劑的不精確性以及嚴重的副作用抑止了TRPV4的阻斷劑的研發。由於A型激酶錨定蛋白（A-kinase anchoring protein 79，AKAP79）可以整合像PKC和PKA等的訊息分子，透過增強磷酸化去調節目標蛋白，以小干擾核糖核酸（small interfering ribonucleic acid; siRNA）可抑制發炎性痛覺過敏。用小干擾核糖核酸抑制AKAP79將是未來深具潛力的止痛藥。

並列關鍵字

瞬時感受器電位離子通道蛋白 ； 瞬時感受器電位香草酸第四亞型離子通道 ； 蛋白蛋白激酶C ； 蛋白激酶A ； 小干擾核糖核酸 ； A型激酶錨定蛋白79