PMC:4195273 / 957-6504 JSONTXT

{"project":"TEST0","denotations":[{"id":"25352770-235-243-357206","span":{"begin":342,"end":346},"obj":"[\"7225368\"]"},{"id":"25352770-235-243-357207","span":{"begin":365,"end":369},"obj":"[\"7891182\"]"},{"id":"25352770-162-170-357208","span":{"begin":534,"end":538},"obj":"[\"15009677\"]"},{"id":"25352770-194-202-357209","span":{"begin":735,"end":739},"obj":"[\"7891182\"]"},{"id":"25352770-220-228-357210","span":{"begin":761,"end":765},"obj":"[\"8647455\"]"},{"id":"25352770-230-238-357211","span":{"begin":1007,"end":1011},"obj":"[\"7891182\"]"},{"id":"25352770-230-238-357212","span":{"begin":1025,"end":1029},"obj":"[\"12584191\"]"},{"id":"25352770-173-181-357213","span":{"begin":1205,"end":1209},"obj":"[\"2017186\"]"},{"id":"25352770-196-204-357214","span":{"begin":1228,"end":1232},"obj":"[\"7891182\"]"},{"id":"25352770-222-230-357215","span":{"begin":1254,"end":1258},"obj":"[\"8647455\"]"},{"id":"25352770-232-240-357216","span":{"begin":1273,"end":1277},"obj":"[\"8987779\"]"},{"id":"25352770-231-239-357217","span":{"begin":1293,"end":1297},"obj":"[\"9419833\"]"},{"id":"25352770-230-238-357218","span":{"begin":1308,"end":1312},"obj":"[\"9667917\"]"},{"id":"25352770-232-240-357219","span":{"begin":1330,"end":1334},"obj":"[\"10420164\"]"},{"id":"25352770-226-234-357220","span":{"begin":1349,"end":1353},"obj":"[\"10077578\"]"},{"id":"25352770-227-235-357222","span":{"begin":1388,"end":1392},"obj":"[\"11058560\"]"},{"id":"25352770-224-232-357223","span":{"begin":1406,"end":1410},"obj":"[\"12584191\"]"},{"id":"25352770-229-237-357224","span":{"begin":1426,"end":1430},"obj":"[\"16800814\"]"},{"id":"25352770-181-189-357225","span":{"begin":1614,"end":1618},"obj":"[\"7891182\"]"},{"id":"25352770-200-208-357226","span":{"begin":1633,"end":1637},"obj":"[\"9654146\"]"},{"id":"25352770-218-226-357227","span":{"begin":1651,"end":1655},"obj":"[\"12584191\"]"},{"id":"25352770-235-243-357228","span":{"begin":1668,"end":1672},"obj":"[\"16716454\"]"},{"id":"25352770-95-103-357229","span":{"begin":1770,"end":1774},"obj":"[\"7891182\"]"},{"id":"25352770-121-129-357230","span":{"begin":1796,"end":1800},"obj":"[\"8647455\"]"},{"id":"25352770-141-149-357231","span":{"begin":1816,"end":1820},"obj":"[\"10612705\"]"},{"id":"25352770-232-240-357232","span":{"begin":1912,"end":1916},"obj":"[\"8647455\"]"},{"id":"25352770-223-231-357233","span":{"begin":1931,"end":1935},"obj":"[\"9654146\"]"},{"id":"25352770-230-238-357234","span":{"begin":1957,"end":1961},"obj":"[\"11567037\"]"},{"id":"25352770-232-240-357235","span":{"begin":1974,"end":1978},"obj":"[\"16716454\"]"},{"id":"25352770-231-239-357236","span":{"begin":2292,"end":2296},"obj":"[\"7891182\"]"},{"id":"25352770-234-242-357237","span":{"begin":2314,"end":2318},"obj":"[\"8710940\"]"},{"id":"25352770-233-241-357238","span":{"begin":2337,"end":2341},"obj":"[\"9243343\"]"},{"id":"25352770-235-243-357239","span":{"begin":2357,"end":2361},"obj":"[\"9419833\"]"},{"id":"25352770-233-241-357240","span":{"begin":2363,"end":2367},"obj":"[\"9527537\"]"},{"id":"25352770-233-241-357241","span":{"begin":2388,"end":2392},"obj":"[\"9590691\"]"},{"id":"25352770-233-241-357243","span":{"begin":2433,"end":2437},"obj":"[\"18314190\"]"},{"id":"25352770-231-239-357244","span":{"begin":2458,"end":2462},"obj":"[\"22030409\"]"},{"id":"25352770-161-169-357245","span":{"begin":2721,"end":2725},"obj":"[\"15659233\"]"},{"id":"25352770-180-188-357246","span":{"begin":2740,"end":2744},"obj":"[\"17913892\"]"},{"id":"25352770-103-111-357247","span":{"begin":2850,"end":2854},"obj":"[\"2417205\"]"},{"id":"25352770-122-130-357248","span":{"begin":2869,"end":2873},"obj":"[\"11979055\"]"},{"id":"25352770-234-242-357249","span":{"begin":3006,"end":3010},"obj":"[\"8990120\"]"},{"id":"25352770-232-240-357250","span":{"begin":3024,"end":3028},"obj":"[\"10868932\"]"},{"id":"25352770-234-242-357251","span":{"begin":3044,"end":3048},"obj":"[\"15746303\"]"},{"id":"25352770-85-93-357252","span":{"begin":3136,"end":3140},"obj":"[\"9590691\"]"},{"id":"25352770-108-116-357253","span":{"begin":3159,"end":3163},"obj":"[\"10766253\"]"},{"id":"25352770-183-191-357254","span":{"begin":3234,"end":3238},"obj":"[\"9883730\"]"},{"id":"25352770-208-216-357255","span":{"begin":3259,"end":3263},"obj":"[\"9590691\"]"},{"id":"25352770-227-235-357256","span":{"begin":3278,"end":3282},"obj":"[\"10468615\"]"},{"id":"25352770-235-243-357257","span":{"begin":3298,"end":3302},"obj":"[\"11241374\"]"},{"id":"25352770-233-241-357258","span":{"begin":3656,"end":3660},"obj":"[\"11043558\"]"},{"id":"25352770-228-236-357259","span":{"begin":3675,"end":3679},"obj":"[\"12958177\"]"},{"id":"25352770-230-238-357260","span":{"begin":3983,"end":3987},"obj":"[\"11223006\"]"},{"id":"25352770-233-241-357261","span":{"begin":4223,"end":4227},"obj":"[\"9806554\"]"},{"id":"25352770-234-242-357262","span":{"begin":4245,"end":4249},"obj":"[\"10905499\"]"},{"id":"25352770-228-236-357263","span":{"begin":4271,"end":4275},"obj":"[\"11522684\"]"},{"id":"25352770-222-230-357264","span":{"begin":4292,"end":4296},"obj":"[\"11791158\"]"},{"id":"25352770-230-238-357266","span":{"begin":4341,"end":4345},"obj":"[\"15823203\"]"},{"id":"25352770-228-236-357267","span":{"begin":4361,"end":4365},"obj":"[\"16210370\"]"},{"id":"25352770-234-242-357268","span":{"begin":4382,"end":4386},"obj":"[\"20151954\"]"},{"id":"25352770-232-240-357269","span":{"begin":4668,"end":4672},"obj":"[\"11567037\"]"},{"id":"25352770-234-242-357270","span":{"begin":4690,"end":4694},"obj":"[\"15908120\"]"},{"id":"25352770-227-235-357271","span":{"begin":4708,"end":4712},"obj":"[\"17569753\"]"},{"id":"25352770-188-196-357272","span":{"begin":4903,"end":4907},"obj":"[\"11567037\"]"},{"id":"25352770-205-213-357273","span":{"begin":5115,"end":5119},"obj":"[\"14759497\"]"},{"id":"25352770-228-236-357274","span":{"begin":5467,"end":5471},"obj":"[\"15908120\"]"}],"text":"Introduction\nExperiments conducted with acute administration of cocaine or amphetamine in rodents resulted in the upregulation of a particular mRNA species in the striatum of the brain that was subsequently named “cocaine- and amphetamine-regulated transcript” (CART) and the encoded peptides are referred to as CART peptides (Spiess et al., 1981; Douglass et al., 1995). Importantly, CART mRNA levels were also found increased in the nucleus accumbens on post-mortem tissues from human victims of cocaine overdose (Albertson et al., 2004). CART is transcribed as two alternatively spliced mRNAs that are of different lengths and hence produce pro-peptides of different lengths, called proCART 1–89 and proCART 1–102 (Douglass et al., 1995; Douglass and Daoud, 1996). However, the mRNA splicing has no effect on the final peptide, as the active parts of the CART peptides are encoded by a sequence that lies downstream of the spliced region and is therefore identical in both pro-peptides (Douglass et al., 1995; Dey et al., 2003). However, the proCART peptides contain several cleavage sites that allow post-translational processing by pro-hormone convertases in a tissue-specific manner (Seidah et al., 1991; Douglass et al., 1995; Douglass and Daoud, 1996; Dong et al., 1997; Koylu et al., 1997; Steiner, 1998; Kuhar and Yoho, 1999; Thim et al., 1999; Vrang et al., 1999a; Dun et al., 2000; Dey et al., 2003; Stein et al., 2006). This processing produces at least two known biologically active peptides, CART I (55–102) and CART II (62–102), each containing three potential disulphide bridges (Douglass et al., 1995; Thim et al., 1998; Dey et al., 2003; Dominguez, 2006).\nCART peptides are evolutionarily strongly conserved between rodent and human (Douglass et al., 1995; Douglass and Daoud, 1996; Adams et al., 1999), with about 95% amino-acid identity between the active neuropeptides (Douglass and Daoud, 1996; Thim et al., 1998; Yermolaieva et al., 2001; Dominguez, 2006), suggestive of a conserved critical physiological function. Notably, high levels of CART expression have been identified to localize in brain regions that include the arcuate nucleus (Arc), the lateral hypothalamus area (LHA), the paraventricular nucleus (PVN), and the nucleus accumbens (Acb) (Douglass et al., 1995; Gautvik et al., 1996; Couceyro et al., 1997; Koylu et al., 1997, 1998; Kristensen et al., 1998; Vrang et al., 1999a; Hubert and Kuhar, 2008; Cavalcante et al., 2011), suggesting an important role for CART in the regulation of food intake and energy homeostasis. This is consistent with results from injections of CART peptide into the nucleus accumbens which have shown an inhibition of feeding in rodents (Yang and Shieh, 2005; Jean et al., 2007). In addition, CART in the Arc is co-localized with α-melanocyte stimulating hormone (α-MSH) (Chronwall, 1985; Adam et al., 2002), which is produced from the proopiomelanocortin (POMC) precursor and is a major inhibitor of appetite and food intake (Fan et al., 1997; Kim et al., 2000; Zheng et al., 2005). In the Arc, CART mRNA levels are regulated by circulating leptin (Kristensen et al., 1998; Schwartz et al., 2000) and are increased by peripheral leptin administration (Elias et al., 1998; Kristensen et al., 1998; Wang et al., 1999; Elias et al., 2001), again indicative of a critical role in energy balance regulation. Moreover, injection of CART I (55–102) into the PVN or Arc of rats markedly enhanced the mRNA expression for the uncoupling protein-1 (UCP-1) in brown adipose tissue, relating CART peptides not only to the control of feeding but also the modulation of energy expenditure (Wang et al., 2000; Kong et al., 2003). Mechanistically, it has been shown that application of CART I (55–102) to hypothalamic explants can stimulate the release of corticotropin-releasing hormone (CRH) and thyrotropin releasing hormone, which further links CART to the regulation of the hypothalamic-pituitary-adrenal axis (Stanley et al., 2001). Importantly, several genetic studies have associated mutations or polymorphisms in the CART gene in humans with obesity, clearly demonstrating a crucial role of CART in the control of energy homeostasis also in humans (Hager et al., 1998; Challis et al., 2000; del Giudice et al., 2001; Yamada et al., 2002; Dominguez et al., 2004a; Guerardel et al., 2005; Yanik et al., 2006; Rigoli et al., 2010).\nWhile a specific CART receptor(s) has not been identified to date, there is strong evidence that CART signaling can be blocked by pertussis toxin (PTX), indicative of the involvement of an inhibitory G-protein-coupling receptor that couples to Gi/o proteins (Yermolaieva et al., 2001; Lakatos et al., 2005; Sen et al., 2007). For example, CART I (55–102) has been described to inhibit voltage-gated L-type Ca2+ channels in hippocampal neurons, an effect that was blocked by treatment with PTX (Yermolaieva et al., 2001). Furthermore, central administration of CART I (55–102) stimulated the phosphorylation of cyclic AMP-response-element-binding protein (CREB) in CRH neurons in the PVN of fasted and fed rats (Sarkar et al., 2004), which again is classified as a PTX-sensitive mechanism. Finally, CART I (55–102) application activated extracellular signal-regulated kinase (ERK) phosphorylation in the rodent pituitary-derived cell lines, AtT20 and GH3, and such CART-induced effects were attenuated by a MEK kinase inhibitor as well as pre-treatment with PTX (Lakatos et al., 2005), further supporting the mediation of CART action by inhibitory G proteins."}

{"project":"0_colil","denotations":[{"id":"25352770-7225368-357206","span":{"begin":342,"end":346},"obj":"7225368"},{"id":"25352770-7891182-357207","span":{"begin":365,"end":369},"obj":"7891182"},{"id":"25352770-15009677-357208","span":{"begin":534,"end":538},"obj":"15009677"},{"id":"25352770-7891182-357209","span":{"begin":735,"end":739},"obj":"7891182"},{"id":"25352770-8647455-357210","span":{"begin":761,"end":765},"obj":"8647455"},{"id":"25352770-7891182-357211","span":{"begin":1007,"end":1011},"obj":"7891182"},{"id":"25352770-12584191-357212","span":{"begin":1025,"end":1029},"obj":"12584191"},{"id":"25352770-2017186-357213","span":{"begin":1205,"end":1209},"obj":"2017186"},{"id":"25352770-7891182-357214","span":{"begin":1228,"end":1232},"obj":"7891182"},{"id":"25352770-8647455-357215","span":{"begin":1254,"end":1258},"obj":"8647455"},{"id":"25352770-8987779-357216","span":{"begin":1273,"end":1277},"obj":"8987779"},{"id":"25352770-9419833-357217","span":{"begin":1293,"end":1297},"obj":"9419833"},{"id":"25352770-9667917-357218","span":{"begin":1308,"end":1312},"obj":"9667917"},{"id":"25352770-10420164-357219","span":{"begin":1330,"end":1334},"obj":"10420164"},{"id":"25352770-10077578-357220","span":{"begin":1349,"end":1353},"obj":"10077578"},{"id":"25352770-11058560-357222","span":{"begin":1388,"end":1392},"obj":"11058560"},{"id":"25352770-12584191-357223","span":{"begin":1406,"end":1410},"obj":"12584191"},{"id":"25352770-16800814-357224","span":{"begin":1426,"end":1430},"obj":"16800814"},{"id":"25352770-7891182-357225","span":{"begin":1614,"end":1618},"obj":"7891182"},{"id":"25352770-9654146-357226","span":{"begin":1633,"end":1637},"obj":"9654146"},{"id":"25352770-12584191-357227","span":{"begin":1651,"end":1655},"obj":"12584191"},{"id":"25352770-16716454-357228","span":{"begin":1668,"end":1672},"obj":"16716454"},{"id":"25352770-7891182-357229","span":{"begin":1770,"end":1774},"obj":"7891182"},{"id":"25352770-8647455-357230","span":{"begin":1796,"end":1800},"obj":"8647455"},{"id":"25352770-10612705-357231","span":{"begin":1816,"end":1820},"obj":"10612705"},{"id":"25352770-8647455-357232","span":{"begin":1912,"end":1916},"obj":"8647455"},{"id":"25352770-9654146-357233","span":{"begin":1931,"end":1935},"obj":"9654146"},{"id":"25352770-11567037-357234","span":{"begin":1957,"end":1961},"obj":"11567037"},{"id":"25352770-16716454-357235","span":{"begin":1974,"end":1978},"obj":"16716454"},{"id":"25352770-7891182-357236","span":{"begin":2292,"end":2296},"obj":"7891182"},{"id":"25352770-8710940-357237","span":{"begin":2314,"end":2318},"obj":"8710940"},{"id":"25352770-9243343-357238","span":{"begin":2337,"end":2341},"obj":"9243343"},{"id":"25352770-9419833-357239","span":{"begin":2357,"end":2361},"obj":"9419833"},{"id":"25352770-9527537-357240","span":{"begin":2363,"end":2367},"obj":"9527537"},{"id":"25352770-9590691-357241","span":{"begin":2388,"end":2392},"obj":"9590691"},{"id":"25352770-18314190-357243","span":{"begin":2433,"end":2437},"obj":"18314190"},{"id":"25352770-22030409-357244","span":{"begin":2458,"end":2462},"obj":"22030409"},{"id":"25352770-15659233-357245","span":{"begin":2721,"end":2725},"obj":"15659233"},{"id":"25352770-17913892-357246","span":{"begin":2740,"end":2744},"obj":"17913892"},{"id":"25352770-2417205-357247","span":{"begin":2850,"end":2854},"obj":"2417205"},{"id":"25352770-11979055-357248","span":{"begin":2869,"end":2873},"obj":"11979055"},{"id":"25352770-8990120-357249","span":{"begin":3006,"end":3010},"obj":"8990120"},{"id":"25352770-10868932-357250","span":{"begin":3024,"end":3028},"obj":"10868932"},{"id":"25352770-15746303-357251","span":{"begin":3044,"end":3048},"obj":"15746303"},{"id":"25352770-9590691-357252","span":{"begin":3136,"end":3140},"obj":"9590691"},{"id":"25352770-10766253-357253","span":{"begin":3159,"end":3163},"obj":"10766253"},{"id":"25352770-9883730-357254","span":{"begin":3234,"end":3238},"obj":"9883730"},{"id":"25352770-9590691-357255","span":{"begin":3259,"end":3263},"obj":"9590691"},{"id":"25352770-10468615-357256","span":{"begin":3278,"end":3282},"obj":"10468615"},{"id":"25352770-11241374-357257","span":{"begin":3298,"end":3302},"obj":"11241374"},{"id":"25352770-11043558-357258","span":{"begin":3656,"end":3660},"obj":"11043558"},{"id":"25352770-12958177-357259","span":{"begin":3675,"end":3679},"obj":"12958177"},{"id":"25352770-11223006-357260","span":{"begin":3983,"end":3987},"obj":"11223006"},{"id":"25352770-9806554-357261","span":{"begin":4223,"end":4227},"obj":"9806554"},{"id":"25352770-10905499-357262","span":{"begin":4245,"end":4249},"obj":"10905499"},{"id":"25352770-11522684-357263","span":{"begin":4271,"end":4275},"obj":"11522684"},{"id":"25352770-11791158-357264","span":{"begin":4292,"end":4296},"obj":"11791158"},{"id":"25352770-15823203-357266","span":{"begin":4341,"end":4345},"obj":"15823203"},{"id":"25352770-16210370-357267","span":{"begin":4361,"end":4365},"obj":"16210370"},{"id":"25352770-20151954-357268","span":{"begin":4382,"end":4386},"obj":"20151954"},{"id":"25352770-11567037-357269","span":{"begin":4668,"end":4672},"obj":"11567037"},{"id":"25352770-15908120-357270","span":{"begin":4690,"end":4694},"obj":"15908120"},{"id":"25352770-17569753-357271","span":{"begin":4708,"end":4712},"obj":"17569753"},{"id":"25352770-11567037-357272","span":{"begin":4903,"end":4907},"obj":"11567037"},{"id":"25352770-14759497-357273","span":{"begin":5115,"end":5119},"obj":"14759497"},{"id":"25352770-15908120-357274","span":{"begin":5467,"end":5471},"obj":"15908120"}],"text":"Introduction\nExperiments conducted with acute administration of cocaine or amphetamine in rodents resulted in the upregulation of a particular mRNA species in the striatum of the brain that was subsequently named “cocaine- and amphetamine-regulated transcript” (CART) and the encoded peptides are referred to as CART peptides (Spiess et al., 1981; Douglass et al., 1995). Importantly, CART mRNA levels were also found increased in the nucleus accumbens on post-mortem tissues from human victims of cocaine overdose (Albertson et al., 2004). CART is transcribed as two alternatively spliced mRNAs that are of different lengths and hence produce pro-peptides of different lengths, called proCART 1–89 and proCART 1–102 (Douglass et al., 1995; Douglass and Daoud, 1996). However, the mRNA splicing has no effect on the final peptide, as the active parts of the CART peptides are encoded by a sequence that lies downstream of the spliced region and is therefore identical in both pro-peptides (Douglass et al., 1995; Dey et al., 2003). However, the proCART peptides contain several cleavage sites that allow post-translational processing by pro-hormone convertases in a tissue-specific manner (Seidah et al., 1991; Douglass et al., 1995; Douglass and Daoud, 1996; Dong et al., 1997; Koylu et al., 1997; Steiner, 1998; Kuhar and Yoho, 1999; Thim et al., 1999; Vrang et al., 1999a; Dun et al., 2000; Dey et al., 2003; Stein et al., 2006). This processing produces at least two known biologically active peptides, CART I (55–102) and CART II (62–102), each containing three potential disulphide bridges (Douglass et al., 1995; Thim et al., 1998; Dey et al., 2003; Dominguez, 2006).\nCART peptides are evolutionarily strongly conserved between rodent and human (Douglass et al., 1995; Douglass and Daoud, 1996; Adams et al., 1999), with about 95% amino-acid identity between the active neuropeptides (Douglass and Daoud, 1996; Thim et al., 1998; Yermolaieva et al., 2001; Dominguez, 2006), suggestive of a conserved critical physiological function. Notably, high levels of CART expression have been identified to localize in brain regions that include the arcuate nucleus (Arc), the lateral hypothalamus area (LHA), the paraventricular nucleus (PVN), and the nucleus accumbens (Acb) (Douglass et al., 1995; Gautvik et al., 1996; Couceyro et al., 1997; Koylu et al., 1997, 1998; Kristensen et al., 1998; Vrang et al., 1999a; Hubert and Kuhar, 2008; Cavalcante et al., 2011), suggesting an important role for CART in the regulation of food intake and energy homeostasis. This is consistent with results from injections of CART peptide into the nucleus accumbens which have shown an inhibition of feeding in rodents (Yang and Shieh, 2005; Jean et al., 2007). In addition, CART in the Arc is co-localized with α-melanocyte stimulating hormone (α-MSH) (Chronwall, 1985; Adam et al., 2002), which is produced from the proopiomelanocortin (POMC) precursor and is a major inhibitor of appetite and food intake (Fan et al., 1997; Kim et al., 2000; Zheng et al., 2005). In the Arc, CART mRNA levels are regulated by circulating leptin (Kristensen et al., 1998; Schwartz et al., 2000) and are increased by peripheral leptin administration (Elias et al., 1998; Kristensen et al., 1998; Wang et al., 1999; Elias et al., 2001), again indicative of a critical role in energy balance regulation. Moreover, injection of CART I (55–102) into the PVN or Arc of rats markedly enhanced the mRNA expression for the uncoupling protein-1 (UCP-1) in brown adipose tissue, relating CART peptides not only to the control of feeding but also the modulation of energy expenditure (Wang et al., 2000; Kong et al., 2003). Mechanistically, it has been shown that application of CART I (55–102) to hypothalamic explants can stimulate the release of corticotropin-releasing hormone (CRH) and thyrotropin releasing hormone, which further links CART to the regulation of the hypothalamic-pituitary-adrenal axis (Stanley et al., 2001). Importantly, several genetic studies have associated mutations or polymorphisms in the CART gene in humans with obesity, clearly demonstrating a crucial role of CART in the control of energy homeostasis also in humans (Hager et al., 1998; Challis et al., 2000; del Giudice et al., 2001; Yamada et al., 2002; Dominguez et al., 2004a; Guerardel et al., 2005; Yanik et al., 2006; Rigoli et al., 2010).\nWhile a specific CART receptor(s) has not been identified to date, there is strong evidence that CART signaling can be blocked by pertussis toxin (PTX), indicative of the involvement of an inhibitory G-protein-coupling receptor that couples to Gi/o proteins (Yermolaieva et al., 2001; Lakatos et al., 2005; Sen et al., 2007). For example, CART I (55–102) has been described to inhibit voltage-gated L-type Ca2+ channels in hippocampal neurons, an effect that was blocked by treatment with PTX (Yermolaieva et al., 2001). Furthermore, central administration of CART I (55–102) stimulated the phosphorylation of cyclic AMP-response-element-binding protein (CREB) in CRH neurons in the PVN of fasted and fed rats (Sarkar et al., 2004), which again is classified as a PTX-sensitive mechanism. Finally, CART I (55–102) application activated extracellular signal-regulated kinase (ERK) phosphorylation in the rodent pituitary-derived cell lines, AtT20 and GH3, and such CART-induced effects were attenuated by a MEK kinase inhibitor as well as pre-treatment with PTX (Lakatos et al., 2005), further supporting the mediation of CART action by inhibitory G proteins."}

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egin":4361,"end":4365},"obj":"16210370"},{"id":"25352770-20151954-38284257","span":{"begin":4382,"end":4386},"obj":"20151954"},{"id":"25352770-11567037-38284258","span":{"begin":4668,"end":4672},"obj":"11567037"},{"id":"25352770-15908120-38284259","span":{"begin":4690,"end":4694},"obj":"15908120"},{"id":"25352770-17569753-38284260","span":{"begin":4708,"end":4712},"obj":"17569753"},{"id":"25352770-11567037-38284261","span":{"begin":4903,"end":4907},"obj":"11567037"},{"id":"25352770-14759497-38284262","span":{"begin":5115,"end":5119},"obj":"14759497"},{"id":"25352770-15908120-38284263","span":{"begin":5467,"end":5471},"obj":"15908120"}],"text":"Introduction\nExperiments conducted with acute administration of cocaine or amphetamine in rodents resulted in the upregulation of a particular mRNA species in the striatum of the brain that was subsequently named “cocaine- and amphetamine-regulated transcript” (CART) and the encoded peptides are referred to as CART peptides (Spiess et al., 1981; Douglass et al., 1995). Importantly, CART mRNA levels were also found increased in the nucleus accumbens on post-mortem tissues from human victims of cocaine overdose (Albertson et al., 2004). CART is transcribed as two alternatively spliced mRNAs that are of different lengths and hence produce pro-peptides of different lengths, called proCART 1–89 and proCART 1–102 (Douglass et al., 1995; Douglass and Daoud, 1996). However, the mRNA splicing has no effect on the final peptide, as the active parts of the CART peptides are encoded by a sequence that lies downstream of the spliced region and is therefore identical in both pro-peptides (Douglass et al., 1995; Dey et al., 2003). However, the proCART peptides contain several cleavage sites that allow post-translational processing by pro-hormone convertases in a tissue-specific manner (Seidah et al., 1991; Douglass et al., 1995; Douglass and Daoud, 1996; Dong et al., 1997; Koylu et al., 1997; Steiner, 1998; Kuhar and Yoho, 1999; Thim et al., 1999; Vrang et al., 1999a; Dun et al., 2000; Dey et al., 2003; Stein et al., 2006). This processing produces at least two known biologically active peptides, CART I (55–102) and CART II (62–102), each containing three potential disulphide bridges (Douglass et al., 1995; Thim et al., 1998; Dey et al., 2003; Dominguez, 2006).\nCART peptides are evolutionarily strongly conserved between rodent and human (Douglass et al., 1995; Douglass and Daoud, 1996; Adams et al., 1999), with about 95% amino-acid identity between the active neuropeptides (Douglass and Daoud, 1996; Thim et al., 1998; Yermolaieva et al., 2001; Dominguez, 2006), suggestive of a conserved critical physiological function. Notably, high levels of CART expression have been identified to localize in brain regions that include the arcuate nucleus (Arc), the lateral hypothalamus area (LHA), the paraventricular nucleus (PVN), and the nucleus accumbens (Acb) (Douglass et al., 1995; Gautvik et al., 1996; Couceyro et al., 1997; Koylu et al., 1997, 1998; Kristensen et al., 1998; Vrang et al., 1999a; Hubert and Kuhar, 2008; Cavalcante et al., 2011), suggesting an important role for CART in the regulation of food intake and energy homeostasis. This is consistent with results from injections of CART peptide into the nucleus accumbens which have shown an inhibition of feeding in rodents (Yang and Shieh, 2005; Jean et al., 2007). In addition, CART in the Arc is co-localized with α-melanocyte stimulating hormone (α-MSH) (Chronwall, 1985; Adam et al., 2002), which is produced from the proopiomelanocortin (POMC) precursor and is a major inhibitor of appetite and food intake (Fan et al., 1997; Kim et al., 2000; Zheng et al., 2005). In the Arc, CART mRNA levels are regulated by circulating leptin (Kristensen et al., 1998; Schwartz et al., 2000) and are increased by peripheral leptin administration (Elias et al., 1998; Kristensen et al., 1998; Wang et al., 1999; Elias et al., 2001), again indicative of a critical role in energy balance regulation. Moreover, injection of CART I (55–102) into the PVN or Arc of rats markedly enhanced the mRNA expression for the uncoupling protein-1 (UCP-1) in brown adipose tissue, relating CART peptides not only to the control of feeding but also the modulation of energy expenditure (Wang et al., 2000; Kong et al., 2003). Mechanistically, it has been shown that application of CART I (55–102) to hypothalamic explants can stimulate the release of corticotropin-releasing hormone (CRH) and thyrotropin releasing hormone, which further links CART to the regulation of the hypothalamic-pituitary-adrenal axis (Stanley et al., 2001). Importantly, several genetic studies have associated mutations or polymorphisms in the CART gene in humans with obesity, clearly demonstrating a crucial role of CART in the control of energy homeostasis also in humans (Hager et al., 1998; Challis et al., 2000; del Giudice et al., 2001; Yamada et al., 2002; Dominguez et al., 2004a; Guerardel et al., 2005; Yanik et al., 2006; Rigoli et al., 2010).\nWhile a specific CART receptor(s) has not been identified to date, there is strong evidence that CART signaling can be blocked by pertussis toxin (PTX), indicative of the involvement of an inhibitory G-protein-coupling receptor that couples to Gi/o proteins (Yermolaieva et al., 2001; Lakatos et al., 2005; Sen et al., 2007). For example, CART I (55–102) has been described to inhibit voltage-gated L-type Ca2+ channels in hippocampal neurons, an effect that was blocked by treatment with PTX (Yermolaieva et al., 2001). Furthermore, central administration of CART I (55–102) stimulated the phosphorylation of cyclic AMP-response-element-binding protein (CREB) in CRH neurons in the PVN of fasted and fed rats (Sarkar et al., 2004), which again is classified as a PTX-sensitive mechanism. Finally, CART I (55–102) application activated extracellular signal-regulated kinase (ERK) phosphorylation in the rodent pituitary-derived cell lines, AtT20 and GH3, and such CART-induced effects were attenuated by a MEK kinase inhibitor as well as pre-treatment with PTX (Lakatos et al., 2005), further supporting the mediation of CART action by inhibitory G proteins."}