Severe acute respiratory syndrome (SARS) is a public health concern worldwide. By studying the human leukocyte antigen (HLA) types A, B, DR, and DQ alleles in 90 Chinese patients with serologically confirmed SARS infections, we identified a strong association between HLA-B*0703 (OR, 4.08; 95% CI, 2.03-8.18;[Bonferroni-corrected P p .00072 P value, P c ! .0022]) and -DRB1*0301 (OR, 0.06; 95%, 0.01-0.47;[after Bonferroni correction, ]) P p .00008 P ! .0042 and the development of SARS. Moreover, the frequency of B*0703 and B60 coinheritance (9.6%; 95% CI, 4.6%-19.0%) in our SARS group was significantly higher ( ) Ϫ9 P p 3 ϫ 10 than that expected in the general population (0.4%). These genetic data will critically affect both the study of the pathogenesis of SARS and the design of vaccination programs.

␥-Aminobutyric acid type B (GABAB) receptors mediate the metabotropic actions of the inhibitory neurotransmitter GABA. These seven-transmembrane receptors are known to signal primarily through activation of G proteins to modulate the action of ion channels or second messengers. The functional GABAB receptor is made up of a heterodimer consisting of two subunits, GABAB-R1 and GABA B-R2, which interact via coiled-coil domains in their C-terminal tails. By using a yeast two-hybrid approach, we have identified direct interactions between the C-terminal tails of GABAB-R1 and GABAB-R2 with two related transcription factors, CREB2 (ATF4) and ATFx. In primary neuronal cultures as well in recombinant Chinese hamster ovary cells expressing GABAB receptors, CREB2 is localized within the cytoplasm as well as the nucleus. Activation of the GABAB receptor by the specific agonist baclofen leads to a marked translocation and accumulation of CREB2 from the cytoplasm into the nucleus. We demonstrate that receptor stimulation results in activation of transcription from a CREB2 responsive reporter gene. Such a signaling mechanism is unique among Family C G protein-coupled receptors and, in the case of the GABAB receptor and CREB2, may play a role in long-term changes in the nervous system. G ABA (␥-aminobutyric acid) is the major inhibitory neurotransmitter activating both ionotrophic GABA A and GABA C receptors as well as metabotropic GABA B receptors (1). GABA B receptors were originally identified pharmacologically (2) and couple through G proteins to Ca 2ϩ or K ϩ channels. Despite being recognized many years ago, the molecular nature of the GABA B receptor has been elucidated only recently (3-8). The initial GABA B ''receptor,'' GABA B -R1, was expression cloned by using a high-affinity antagonist and showed homology to Family C G protein-coupled receptors (GPCRs), such as metabotropic glutamate receptors, with a characteristically large extracellular N-terminal domain as well as a seven-transmembrane topology (3). However, when expressed recombinantly, GABA B -R1 failed to reproduce the expected agonist affinities (3, 5) and was not expressed at the cell surface (5, 9), suggesting that a component was lacking from GABA B -R1 for reconstitution of the functional receptor. Subsequent studies confirmed that a second distinct but related GPCR, GABA B -R2, heterodimerizes with GABA B -R1 to create the GABA B -receptor (4-8). Yeast two-hybrid (YTH) studies showed that the two receptors interact through a coiled-coil domain within their respective C-terminal tails (5, 7, 10), and in situ hybridization analysis showed colocalization of the two receptors (4, 5, 7, 10). The expressed heterodimer reproduced expected agonist pharmacology, and in the presence of GABA B -R2, GABA B -R1 was trafficked to the cell surface. Moreover, effector couplings to K ϩ and Ca 2ϩ channels have now been demonstrated by using the heterodimeric receptor (4,6,11,12).We previously used a YTH screen to identify GABA B -R2 as an interacting protein partner to G...

Recently, evidence has emerged that seven transmembrane G protein-coupled receptors may be present as homo-and heteromers in the plasma membrane. Here we describe a new molecular and functional interaction between two functionally unrelated types of G proteincoupled receptors, namely the metabotropic glutamate type 1␣ (mGlu 1␣ receptor) and the adenosine A1 receptors in cerebellum, primary cortical neurons, and heterologous transfected cells. Co-immunoprecipitation experiments showed a close and subtype-specific interaction between mGlu 1␣ and A1 receptors in both rat cerebellar synaptosomes and co-transfected HEK-293 cells. By using transiently transfected HEK-293 cells a synergy between mGlu 1␣ and A1 receptors in receptorevoked [Ca 2؉ ] i signaling has been shown. In primary cultures of cortical neurons we observed a high degree of co-localization of the two receptors, and excitotoxicity experiments in these cultures also indicate that mGlu 1␣ and A1 receptors are functionally related. Our results provide a molecular basis for adenosine/glutamate receptors cross-talk and open new perspectives for the development of novel agents to treat neuropsychiatric disorders in which abnormal glutamatergic neurotransmission is involved.Glutamate is the major excitatory neurotransmitter in the central nervous system (1), and its function through ionotropic and metabotropic (mGlu) 1 glutamate receptors can be modulated by other neurotransmitters/neuromodulators (2). Eight members of the mGlu receptor family have been identified and categorized into three subgroups on the basis of their sequence homology, agonist selectivity, and signal transduction pathway. Group I contains mGlu 1 and mGlu 5 subtypes, which are coupled to phospholipase C in transfected cells, and have quisqualic acid as their most potent agonist. Five splice variants of mGlu1 receptor have been described, mGlu 1␣ , mGlu 1␤ , mGlu 1c , mGlu 1d , and mGlu 1e receptors (3, 4), all of them differing in the length of their C-terminal tail. The functional significance of the different splice variants has not yet been fully explored. It has been suggested that the C-terminal tail, which is intracellular, might play a role in the subcellular targeting of the receptor (5). Recently, we have reported that the C terminus of mGlu 1␣ receptor interacts with tubulin (6) and that it can regulate the cell surface expression of the receptor (7) and its plasma membrane anchoring (8, 9).Adenosine is an important neuromodulator implicated in a variety of brain activities, particularly those related to sleep and ischemic-hypoxic episodes (10). This ubiquitous nucleoside exerts its actions via specific receptors, four of which (A1, A2A, A2B, and A3) have been cloned (11). The A1R is functionally coupled to members of the pertussis toxin-sensitive family of G proteins (G i1 , G i2 , G i3 , and G o ), and its activation regulates several membrane and intracellular proteins such as adenylate cyclase, Ca 2ϩ channels, K ϩ channels, and phospholipase C (11). Of the multiple neurophys...

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Pulmonary alveoli are formed, in part, by subdivision (septation) of the gas-exchange saccules of the immature lung. Septation is developmentally regulated, and failure to septate at the appropriate time is not followed by delayed spontaneous septation. We report retinoic acid receptor (RAR) beta knockout mice exhibit premature septation; in addition, they form alveoli twice as fast as wild-type mice during the period of septation but at the same rate as wild-type mice thereafter. Consistent with the perinatal effect of RARbeta knockout, RARbeta agonist treatment of newborn rats impairs septation. These results 1) identify RARbeta as the first recognized endogenous signaling that inhibits septation, 2) demonstrate premature onset of septation may be induced, and 3) show the molecular signaling regulating alveolus formation differs during and after the period of septation. Suppressing perinatal RARbeta signaling by RARbeta antagonists may offer a novel, nonsurgical, means of preventing, or remediating, failed septation in prematurely born children.