A FAAH-Regulated Class of N-Acyl Taurines That Activates TRP Ion Channels
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- 作者：Alan Saghatelian ; Michele K. McKinney ; Michael Bandell ; Ardem Patapoutian ; Benjamin F. Cravatt
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：August 1, 2006
- 年：2006
- 卷：45
- 期：30
- 页码：9007 - 9015
- 全文大小：210K
- 年卷期：v.45,no.30(August 1, 2006)
- ISSN：1520-4995
文摘
Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that catabolizes severalbioactive lipids in vivo. Most of the physiological substrates of FAAH characterized to date belong to theN-acyl ethanolamine (NAE) class of fatty acid amides, including the endocannabinoid anandamide, theanti-inflammatory lipid N-palmitoyl ethanolamine, and the satiating factor N-oleoyl ethanolamine. Werecently identified a second structural class of fatty acid amides regulated by FAAH in vivo: the N-acyltaurines (NATs). Global metabolite profiling revealed high concentrations of long chain (
C20) saturatedNATs in the central nervous system (CNS) of FAAH(-/-) mice. Here, we use metabolite profiling tocharacterize the FAAH-NAT system in peripheral mouse tissues. Livers and kidneys of FAAH(-/-)mice possessed dramatic elevations in NATs, which, in contrast to those detected in the CNS, were enrichedin polyunsaturated acyl chains (e.g., C20:4, C22:6). Peripheral NATs rose more than 10-fold within 1 hfollowing pharmacological inactivation of FAAH and reached levels up to ~5000 pmol/g tissue (C22:6in kidney), implicating a constitutive and highly active pathway for NAT metabolism in which FAAHplays an integral part. Interestingly, NATs were found to activate multiple members of the transient receptorpotential (TRP) family of calcium channels, including TRPV1 and TRPV4, which are both expressed inkidney. The dramatic elevation in endogenous levels of NATs following acute or chronic inactivation ofFAAH, in conjunction with the pharmacological effects of these lipids on TRP channels, suggests theexistence of a second major lipid signaling system regulated by FAAH in vivo.
C20) saturatedNATs in the central nervous system (CNS) of FAAH(-/-) mice. Here, we use metabolite profiling tocharacterize the FAAH-NAT system in peripheral mouse tissues. Livers and kidneys of FAAH(-/-)mice possessed dramatic elevations in NATs, which, in contrast to those detected in the CNS, were enrichedin polyunsaturated acyl chains (e.g., C20:4, C22:6). Peripheral NATs rose more than 10-fold within 1 hfollowing pharmacological inactivation of FAAH and reached levels up to ~5000 pmol/g tissue (C22:6in kidney), implicating a constitutive and highly active pathway for NAT metabolism in which FAAHplays an integral part. Interestingly, NATs were found to activate multiple members of the transient receptorpotential (TRP) family of calcium channels, including TRPV1 and TRPV4, which are both expressed inkidney. The dramatic elevation in endogenous levels of NATs following acute or chronic inactivation ofFAAH, in conjunction with the pharmacological effects of these lipids on TRP channels, suggests theexistence of a second major lipid signaling system regulated by FAAH in vivo.