Mapping of calmodulin and G beta gamma binding domains within the C-terminal region of the metabotropic glutamate receptor 7A

Ca2+/calmodulin (Ca2+/CaM) and the subunits of heterotrimeric G-proteins (G) have recently been shown to interact in a mutually exclusive fashion with the intracellular C terminus of the presynaptic metabotropic glutamate receptor 7 (mGluR 7). Here, we further characterized the core CaM and G binding sequences. In contrast to a previous report, we find that the CaM binding motif localized in the N-terminal region of the cytoplasmic tail domain of mGluR 7 is conserved in the related group III mGluRs 4A and 8 and allows these receptors to also bind Ca2+/CaM. Mutational analysis of the Ca2+/CaM binding motif is consistent with group III receptors containing a conventional CaM binding site formed by an amphipathic -helix. Substitutions adjacent to the core CaM target sequence selectively prevent G binding, suggesting that the CaM-dependent regulation of signal transduction involves determinants that overlap with but are different from those mediating G recruitment. In addition, we present evidence that G uses distinct nonoverlapping interfaces for interaction with the mGluR 7 C-terminal tail and the effector enzyme adenylyl cyclase II, respectively. Although G-mediated signaling is abolished in receptors lacking the core CaM binding sequence, subunit activation, as assayed by agonist-dependent GTPS binding, was not affected. This suggests that Ca2+/CaM may alter the mode of group III mGluR signaling from mono- () to bidirectional ( and ) activation of downstream effector cascades. <br/

Smouldering multiple sclerosis: the 'real MS'

Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the ‘real MS’ is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of ‘no evident inflammatory disease activity’ (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes