Norleucine1-Angiotensin IV alleviates mecamylamine-induced spatial memory deficits

Olson, Mikel L.; Olson, Emily A; Qualls, Jacob H; Stratton, Jessica J; Harding, Joseph W.; Wright, John W.

doi:10.1016/j.peptides.2003.12.005

Cited by 43 publications

(27 citation statements)

References 42 publications

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“…In terms of function, intracranially administered AngIV and its functional analogs facilitate memory in rodent behavior models (Braszko et al, 1988;Wright et al, 1993;Tchekalarova et al, 2001;Lee et al, 2003). AngIV also facilitates reversal of memory shortfalls produced by scopolamine, mecamylamine, abusive alcohol dose, ischemia, as well as by disruption of the perforant path in the hippocampus (Borawska et al, 1989;Wright et al, 1996;Pederson et al, 1998;Albiston et al, 2004a;Olson et al, 2004). AngIV enhances neuronal long-term potentiation in vitro and in vivo (Kramar et al, 2001;Wayner et al, 2001) as well as attenuates PTZinduced seizures (Tchekalarova et al, 2001;Stragier et al, 2006) and protects against cerebral ischemia (Faure et al, 2006a(Faure et al, ,b, 2008.…”

Section: E Distribution Of the Of Angiv Binding Sitesmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

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Section: E Distribution Of the Of Angiv Binding Sitesmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

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“…Intracerebroventricular administration of the nAChR antagonist mecamylamine also interferes with spatial memory performance in rats similarly to the mAChR antagonist scopolamine. Interestingly, Norleucine-Ang IV attenuates mecamylamine-induced deficits in spatial memory (Olson et al 2004). Therefore, cognitive facilitation by Ang IV could be attributable to the potentiation of cholinergic neurotransmission.…”

Section: Signal Transduction and Functional Consequencesmentioning

confidence: 96%

The CNS renin-angiotensin system

2006

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The renin-angiotensin system (RAS) is one of the best-studied enzyme-neuropeptide systems in the brain and can serve as a model for the action of peptides on neuronal function in general. It is now well established that the brain has its own intrinsic RAS with all its components present in the central nervous system. The RAS generates a family of bioactive angiotensin peptides with variable biological and neurobiological activities. These include angiotensin-(1-8) [Ang II], angiotensin-(3-8) [Ang IV], and angiotensin-(1-7) [Ang-(1-7)]. These neuroactive forms of angiotensin act through specific receptors. Only Ang II acts through two different high-specific receptors, termed AT1 and AT2. Neuronal AT1 receptors mediate the stimulatory actions of Ang II on blood pressure, water and salt intake, and the secretion of vasopressin. In contrast, neuronal AT2 receptors have been implicated in the stimulation of apoptosis and as being antagonistic to AT1 receptors. Among the many potential effects mediated by stimulation of AT2 are neuronal regeneration after injury and the inhibition of pathological growth. Ang-(1-7) mediates its antihypertensive effects by stimulating the synthesis and release of vasodilator prostaglandins and nitric oxide and by potentiating the hypotensive effects of bradykinin. New data concerning the roles of Ang IV and Ang-(1-7) in cognition also support the existence of complex site-specific interactions between multiple angiotensins and multiple receptors in the mediation of important central functions of the RAS. Thus, the RAS of the brain is involved not only in the regulation of blood pressure, but also in the modulation of multiple additional functions in the brain, including processes of sensory information, learning, and memory, and the regulation of emotional responses.

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“…This indicates broad substrate specificity, although the main identified substrates for IRAP contain either a tyrosine or phenylalanine at or near the amino terminus of the peptide. Pharmacological inhibition of IRAP in the brain improves memory in normal rodents (Lee et al, 2004;Albiston et al, 2008) and in animals with memory deficits induced by a range of perturbations (Wisniewski et al, 1993;Krishnan et al, 1999), including chemical disruption of the septohippocampal cholinergic pathway (Pederson et al, 1998(Pederson et al, , 2001Albiston et al, 2004a;Olson et al, 2004). More recently, inhibition of aminopeptidase activity of IRAP in the brain has been linked to anticonvulsant properties (Stragier et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Phenylalanine-544 Plays a Key Role in Substrate and Inhibitor Binding by Providing a Hydrophobic Packing Point at the Active Site of Insulin-Regulated Aminopeptidase

Albiston¹,

Pham²,

Ye³

et al. 2010

Molecular Pharmacology

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Inhibitors of insulin-regulated aminopeptidase (IRAP) improve memory and are being developed as a novel treatment for memory loss. In this study, the binding of a class of these inhibitors to human IRAP was investigated using molecular docking and sitedirected mutagenesis. Four benzopyran-based IRAP inhibitors with different affinities were docked into a homology model of the catalytic site of IRAP. Two 4-pyridinyl derivatives orient with the benzopyran oxygen interacting with the Zn 2ϩ ion and a direct parallel ring-stack interaction between the benzopyran rings and Phe544. In contrast, the two 4-quinolinyl derivatives orient in a different manner, interacting with the Zn 2ϩ ion via the quinoline nitrogen, and Phe544 contributes an edge-face hydrophobic stacking point with the benzopyran moiety. Mutagenic replacement of Phe544 with alanine, isoleucine, or valine resulted in either complete loss of catalytic activity or altered hydrolysis velocity that was substrate-dependent. Phe544 is also important for inhibitor binding, because these mutations altered the K i in some cases, and docking of the inhibitors into the corresponding Phe544 mutant models revealed how the interaction might be disturbed. These findings demonstrate a key role of Phe544 in the binding of the benzopyran IRAP inhibitors and for optimal positioning of enzyme substrates during catalysis.

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Norleucine1-Angiotensin IV alleviates mecamylamine-induced spatial memory deficits

Cited by 43 publications

References 42 publications

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

The CNS renin-angiotensin system

Phenylalanine-544 Plays a Key Role in Substrate and Inhibitor Binding by Providing a Hydrophobic Packing Point at the Active Site of Insulin-Regulated Aminopeptidase

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