TRPV1受体和信号转导

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Rosenbaum T,西蒙SA

TRPV1受体和信号转导

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PubMed ID
21204507 (在PubMed
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文摘

痛感时全身神经信号来自痛觉受器的终端传播到二阶脊髓和脑干神经元,于是他们被传输到特定的高阶脑区(价格,2000)。最近的研究已开始阐明一些分子机制的潜在的有害刺激的传导。发现了许多刺激激活离子通道出现在伤害感受器终端作为分子传感器这些神经元去极化,从而引发痛觉冲动沿着疼痛通路(价格,2000;科斯蒂根和伍尔夫,2000)。这些离子通道中瞬时受体电位(TRP)的成员的家庭。到目前为止,研究最多的TRP家族的成员是TRPV1受体。这是因为它是唯一一个激活辣椒素,辣椒的复合负责其“热”的味道;此外,抑制TRPV1已被证明有治疗价值(DiMarzo et al ., 2002;Cortright Szallasi, 2004)。尽管我们将关注这些通道在痛觉受器的存在,我们注意到,他们已确定在其他细胞类型和在各种皮质和皮质下区域(托斯et al ., 2005)。 The transient receptor potential vanilloid 1 (TRPV1) channel is predicted to have six transmembrane domains and a short, pore-forming hydrophobic stretch between the fifth and sixth transmembrane domains (see Figure 5.1A). It is activated not only by the vanilloid capsaicin (Caterina et al., 1997), but also by noxious heat (>43 degrees C) and low pH (Caterina et al., 1997; Tominaga et al., 1998), voltage (Gunthorpe et al., 2000; Piper et al., 1999), and various lipids (Julius and Basbaum, 2001; Caterina and Julius, 2001; Clapham, 2003; Cortright and Szallasi, 2004, Szallasi and Blumberg, 1999; Prescott and Julius, 2003; Jung et al., 2004; Bhave et al., 2003). In cells, TRPV1 is inactivated by its binding to PIP2 and is released from this block by PLC-mediated PIP2 hydrolysis (Prescott and Julius, 2003). Since its cloning in 1997, many amino acid regions within the TPRV1 protein have been shown to be involved in specific functions, such as capsaicin, proton, and heat activation; voltage dependence; permeability and ion selectivity; antagonist regions; desensitization; phosphorylation; modulation by lipids; and multimerization. In regard to its subunit composition, functional TRPV1 channels likely exist as homomeric or heteromeric complexes composed of four subunits that assemble to form functional cation-(including calcium) permeable pores (Clapham, 2003; Kedei et al., 2001; Kuzhikanathil et al., 2001). Moreover, like other ion channels, these channels have been shown to be associated with regulatory proteins (see Figure 5.1B and Kim et al., 2006). There are many signaling pathways that become activated (or inhibited) by the activation of TRPV1 (Farkas-Szallasi et al., 1995; Wood et al., 1988). Similar to many other channels, TRPV1 contains multiple phosphorylation sites in its amino acid sequence for protein kinase C (PKC) (Bhave et al., 2003; Dai et al., 2004; Premkumar et al., 2004), protein kinase A (PKA) (Bhave et al., 2002; De Petrocellis et al., 2001; Rathee et al., 2002) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). The presence of multiple phosphorylation sites in TRPV1 implies possible regulatory actions by these kinases (Wood et al., 1988). Discussed later in this chapter are several lines of evidence that show that two types of lipids-endocannabinoids and eicosanoids that are products of lipoxygenase (LOX)-activate TRPV1 channels (Zygmunt et al., 1999; Hwang et al., 2000). Because TRPV1 functions as a molecular integrator for multiple types of sensory input, in this chapter we will explore the molecular mechanisms underlying the activation and modulation of this channel.

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