RESUMEN
Cannabinoid receptor interacting protein 1a (CRIP1a) modulates CB1 cannabinoid receptor G-protein coupling in part by altering the selectivity for Gαi subtype activation, but the molecular basis for this function of CRIP1a is not known. We report herein the first structure of CRIP1a at a resolution of 1.55 Å. CRIP1a exhibits a 10-stranded and antiparallel ß-barrel with an interior comprised of conserved hydrophobic residues and loops at the bottom and a short helical cap at the top to exclude solvent. The ß-barrel has a gap between strands ß8 and ß10, which deviates from ß-sandwich fatty acid-binding proteins that carry endocannabinoid compounds and the Rho-guanine nucleotide dissociation inhibitor predicted by computational threading algorithms. The structural homology search program DALI identified CRIP1a as homologous to a family of lipidated-protein carriers that includes phosphodiesterase 6 delta subunit and Unc119. Comparison with these proteins suggests that CRIP1a may carry two possible types of cargo: either (i) like phosphodiesterase 6 delta subunit, cargo with a farnesyl moiety that enters from the top of the ß-barrel to occupy the hydrophobic interior or (ii) like Unc119, cargo with a palmitoyl or a myristoyl moiety that enters from the side where the missing ß-strand creates an opening to the hydrophobic pocket. Fluorescence polarization analysis demonstrated CRIP1a binding of an N-terminally myristoylated 9-mer peptide mimicking the Gαi N terminus. However, CRIP1a could not bind the nonmyristolyated Gαi peptide or cargo of homologs. Thus, binding of CRIP1a to Gαi proteins represents a novel mechanism to regulate cell signaling initiated by the CB1 receptor.
Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas Portadoras/ultraestructura , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Secuencia de Aminoácidos , Animales , Cannabinoides/metabolismo , Proteínas Portadoras/genética , Endocannabinoides , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/ultraestructura , Proteínas de la Membrana/metabolismo , Ratones , Péptidos/metabolismo , Unión Proteica , Conformación Proteica , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB1/ultraestructura , Receptores de Cannabinoides/metabolismo , Receptores de Cannabinoides/ultraestructuraRESUMEN
Endocannabinoid signaling depends upon the CB1 and CB2 cannabinoid receptors, their endogenous ligands anandamide and 2-arachidonoylglycerol, and intracellular proteins that mediate responses via the C-terminal and other intracellular receptor domains. The CB1 receptor regulates and is regulated by associated G proteins predominantly of the Gi/o subtypes, ß-arrestins 1 and 2, and the cannabinoid receptor-interacting protein 1a (CRIP1a). Evidence for a physiological role for CRIP1a is emerging as data regarding the cellular localization and function of CRIP1a are generated. Here we summarize the neuronal distribution and role of CRIP1a in endocannabinoid signaling, as well as discuss investigations linking CRIP1a to development, vision and hearing sensory systems, hippocampus and seizure regulation, and psychiatric disorders including schizophrenia. We also examine the genetic and epigenetic association of CRIP1a within a variety of cancer subtypes. This review provides evidence upon which to base future investigations on the function of CRIP1a in health and disease.
Asunto(s)
Neoplasias/metabolismo , Receptores de Cannabinoides/metabolismo , Esquizofrenia/metabolismo , Convulsiones/metabolismo , Animales , HumanosRESUMEN
People's self-concepts are subject to change through various processes, one of which is self-expansion. Self-expansion is a motivation to increase one's self-concept through engaging in novel, exciting, and interesting activities or by taking on one's partner's qualities. Despite the plethora of research on self-expansion, there has not been much work on whether people vary in their desire to expand. This study validates a new measure, called the Self-Expansion Preference Scale, to examine people's differing motivation for self-expansion. The sample included 611 participants who responded to 24 items, 12 of which pertained to self-expansion, a desire to increase the self-concept, and 12 of which pertained to self-conservation, a desire to maintain the self-concept. After reverse coding the 12 conserver items, an exploratory and confirmatory factor analysis indicated that there was a single dominant factor of self-expansion. The single-factor scale positively correlated with a series of both convergent measures (e.g., openness to experience) and predictive measures (e.g., hedonic well-being). Ultimately, the Self-Expansion Preference Scale offers new insight into a well-established process in an easily administered format. Looking forward, it would be interesting to see the implications of the scale as applied to romantic relationships, where self-expansion was initially researched.