Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pituitary adenylate cyclase-activating polypeptide (PACAP, Adcyap1) activation of PAC1 receptors (Adcyap1r1) significantly increases excitability of guinea pig cardiac neurons. This modulation of excitability is mediated in part by plasma membrane G protein-dependent activation of adenylyl cyclase and downstream signaling cascades, as well as by endosomal signaling mechanisms. PACAP/PAC1 receptor-mediated activation of plasma membrane adenylyl cyclase (AC) and the resulting increase in cellular cAMP enhances a hyperpolarization-induced nonselective cationic current Ih, which contributes to the PACAP-induced increase in cardiac neuron excitability. Further, PACAP-mediated AC/cAMP/PKA downstream signaling also appears to enhance cardiac neuron IT to facilitate the excitatory responses. PACAP activation of PAC1 receptors rapidly stimulates receptor internalization, and reducing ambient temperature or treatments with the clathrin inhibitor Pitstop2 or the dynamin I/II inhibitor dynasore to block endocytic events can suppress PACAP-enhanced neuronal excitability. Thus, endocytosis inhibitors essentially eliminate PACAP-enhanced excitability suggesting that endosomal platforms represent a primary signaling mechanism. Endosomal signaling is associated canonically with ERK activation and in accord, PACAP-enhanced cardiac neuron excitability is reduced by MEK inhibitor pretreatments. PACAP activation of MEK/ERK signaling can enhance currents through voltage-dependent Nav1.7 channels. Hence, PACAP-induced PAC1 receptor internalization/endosomal signaling, recruitment of MEK/ERK signaling, and modulation of Nav1.7 are implicated as key mechanisms contributing to the PACAP-enhanced neuronal excitability. PACAP/PAC1 receptor-mediated endosomal ERK signaling in central circuits can play key roles in development of chronic pain and anxiety-related responses; thus, PAC1 endosomal signaling likely participates in a variety of homeostatic responses within neuronal circuits in the CNS.
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PMID:PACAP-Induced PAC1 Receptor Internalization and Recruitment of Endosomal Signaling Regulate Cardiac Neuron Excitability. 3005 97

While addiction to drugs of abuse represents a significant health problem worldwide, the behavioral and neural mechanisms that underlie addiction and relapse are largely unclear. The concept of the dark side of addiction, developed and explored by George Koob and colleagues, describes a systematic decrease in reward-related processing following drug self-administration and subsequent recruitment of anti-reward (i.e., stress) systems. Indeed, the activation of central nervous system (CNS) stress-response systems by drugs of abuse is contributory not only to mood and anxiety-related disorders but critical to both the maintenance of addiction and relapse following abstinence. In both human and animal studies, compounds that activate the bed nucleus of the stria terminalis (BNST) have roles in stress-related behaviors and addiction processes. The activation of pituitary adenylate cyclase-activating peptide (PACAP) systems in the BNST mediates many consequences of chronic stressor exposure that may engage in part downstream corticotropin-releasing hormone (CRH) signaling. Similar to footshock stress, the BNST administration of PACAP or the PAC1 receptor-specific agonist maxadilan can facilitate relapse following extinction of cocaine-seeking behavior. Further, in the same paradigm, the footshock-induced relapse could be attenuated following BNST pretreatment with PAC1 receptor antagonist PACAP6-38, implicating PACAP systems as critical components underlying stress-induced reinstatement. In congruence with previous work, the PAC1 receptor internalization and endosomal MEK/ERK signaling appear contributory mechanisms to the addiction processes. The studies offer new insights and approaches to addiction and relapse therapeutics.
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PMID:Pituitary Adenylate Cyclase-Activating Peptide (PACAP) Signaling and the Dark Side of Addiction. 3007 72

The pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor (PAC1R, ADCYAP1R1) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of G protein-coupled receptors (GPCRs). PAC1R has been shown to play crucial roles in the central and peripheral nervous systems. The activation of PAC1R initiates diverse downstream signal transduction pathways, including adenylyl cyclase, phospholipase C, MEK/ERK, and Akt pathways that regulate a number of physiological systems to maintain functional homeostasis. Accordingly, at times of tissue injury or insult, PACAP/PAC1R activation of these pathways can be trophic to blunt or delay apoptotic events and enhance cell survival. Enhancing PAC1R signaling under these conditions has the potential to mitigate cellular damages associated with cerebrovascular trauma (including stroke), neurodegeneration (such as Parkinson's and Alzheimer's disease), or peripheral organ insults. Conversely, maladaptive PACAP/PAC1R signaling has been implicated in a number of disorders, including stressrelated psychopathologies (i.e., depression, posttraumatic stress disorder, and related abnormalities), chronic pain and migraine, and metabolic diseases; abrogating PAC1R signaling under these pathological conditions represent opportunities for therapeutic intervention. Given the diverse PAC1R-mediated biological activities, the receptor has emerged as a relevant pharmaceutical target. In this review, we first describe the current knowledge regarding the molecular structure, dynamics, and function of PAC1R. Then, we discuss the roles of PACAP and PAC1R in the activation of a variety of signaling cascades related to the physiology and diseases of the nervous system. Lastly, we examine current drug design and development of peptides and small molecules targeting PAC1R based on a number of structure- activity relationship studies and key pharmacophore elements. At present, the rational design of PAC1R-selective peptide or small-molecule therapeutics is largely hindered by the lack of structural information regarding PAC1R activation mechanisms, the PACAP-PAC1R interface, and the core segments involved in receptor activation. Understanding the molecular basis governing the PACAP interactions with its different cognate receptors will undoubtedly provide a basis for the development and/or refinement of receptor-selective therapeutics.
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PMID:Targeting the PAC1 Receptor for Neurological and Metabolic Disorders. 3128 62


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