Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually presents with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. The aim of management is to induce and then maintain remission, defined as resolution of symptoms and endoscopic healing. Treatments for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immunosuppressants. Some patients can require colectomy for medically refractory disease or to treat colonic neoplasia. The therapeutic armamentarium for ulcerative colitis is expanding, and the number of drugs with new targets will rapidly increase in coming years.

Dendritic spines receive the vast majority of excitatory synaptic contacts in the mammalian brain and are presumed to contain machinery for the integration of various signal transduction pathways. Protein phosphatase 1 (PP1) is greatly enriched in dendritic spines and has been implicated in both the regulation of ionic conductances and long-term synaptic plasticity. The molecular mechanism whereby PP1 is localized to spines is unknown. We have now characterized a novel protein that forms a complex with the catalytic subunit of PP1 and is a potent modulator of PP1 enzymatic activity in vitro. Within the brain this protein displays a remarkably distinct localization to the heads of dendritic spines and has therefore been named spinophilin. Spinophilin has the properties expected of a scaffolding protein localized to the cell membrane and contains a single consensus sequence in PSD95͞DLG͞zo-1, which implies cross-linking of PP1 to transmembrane protein complexes. We propose that spinophilin represents a novel targeting subunit for PP1, which directs the enzyme to those substrates in the dendritic spine compartment, e.g., neurotransmitter receptors, which mediate the regulation of synaptic function by PP1.

Spinophilin, a protein that interacts with actin and protein phosphatase-1, is highly enriched in dendritic spines. Here, through the use of spinophilin knockout mice, we provide evidence that spinophilin modulates both glutamatergic synaptic transmission and dendritic morphology. The ability of protein phosphatase-1 to regulate the activity of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors was reduced in spinophilin knockout mice. Consistent with altered glutamatergic transmission, spinophilin-deficient mice showed reduced long-term depression and exhibited resistance to kainate-induced seizures and neuronal apoptosis. In addition, deletion of the spinophilin gene caused a marked increase in spine density during development in vivo as well as altered filopodial formation in cultured neurons. In conclusion, spinophilin appears to be required for the regulation of the properties of dendritic spines. D endritic spines are specialized protrusions from dendritic shafts that receive the vast majority of excitatory input in the central nervous system (1). Dynamic changes in the number, size, and shape of dendritic spines have been associated with learning (2, 3), electrophysiological (4-6), developmental (7,8), and hormonal changes (9, 10). It is increasingly evident that alterations in synaptic activity can cause morphological changes of dendritic spines (2,(11)(12)(13)(14): high-intensity stimulation of CA1 neurons induces rapid formation of spine-like protrusions (or filopodia) (12), and decreased synaptic activity results in loss of dendritic spines (14). Conversely, morphological changes in dendritic spines have profound effects on their electrical and biochemical properties (15-17), thereby regulating the efficacy of synaptic transmission (13,18,19). However, with the exception of evidence that localization of glutamate receptors is altered with neuronal activity (20, 21), little is known about the molecular mechanisms underlying the linkage between synaptic activity and the dynamic morphological changes of dendritic spines.Spinophilin, also called neurabin II (22), interacts with several proteins that are highly enriched in spines (22,23). One of them, actin, is important for the formation, maintenance, and morphology of spines (18). In vitro, spinophilin bundles actin filaments (22), suggesting its possible role as one organizer of the actin-based cytoskeleton in dendritic spines. Another binding partner of spinophilin that is enriched in dendritic spines is protein phosphatase-1 (PP-1) (23, 24). There is evidence that PP-1 modulates the activity of a variety of ion channels, including glutamate receptors (25-28). These properties of spinophilin make it an attractive candidate for regulating the dynamic morphological and functional changes that occur in dendritic spines. To investigate the possible role of spinophilin in spine formation and function, we used gene-targeting methods to generate mice that lack the expression of spinophilin. MethodsGeneration ...