Acid-sensing ion channel (ASIC) subunits associate to form homomeric or heteromeric proton-gated ion channels in neurons throughout the nervous system. The ASIC1a subunit plays an important role in establishing the kinetics of proton-gated currents in the central nervous system and activation of ASIC1a homomeric channels induces neuronal death following local acidosis that accompanies cerebral ischemia. The ASIC2b subunit is expressed in the brain in a pattern that overlaps ASIC1a, yet the contribution of ASIC2b has remained elusive. We find that co-expression of ASIC2b with ASIC1a in Xenopus oocytes results in novel proton-gated currents with properties distinct from ASIC1a homomeric channels. In particular, ASIC2b/1a heteromeric channels are inhibited by the non-selective potassium channel blockers tetraethylammonium (TEA) and barium. In addition, steady-state desensitization is induced at more basic pH values and Big Dynorphin sensitivity is enhanced in these unique heteromeric channels. Cultured hippocampal neurons show proton-gated currents consistent with ASIC2b contribution and these currents are lacking in neurons from mice with an ACCN1 (ASIC2) gene disruption. Finally, we find that these ASIC2b/1a heteromeric channels contribute to acidosis-induced neuronal death. Together, our results show that ASIC2b confers unique properties to heteromeric channels in central neurons. Further, these data indicate that ASIC2, like ASIC1, plays a role in acidosis-induced neuronal death and implicate the ASIC2b/1a subtype as a novel pharmacological target to prevent neuronal injury following stroke.
Primary cilia are nearly ubiquitous cellular appendages that provide important sensory and signaling functions. Ciliary dysfunction underlies numerous human diseases, collectively termed ciliopathies. Primary cilia have distinct functions on different cell types and these functions are defined by the signaling proteins that localize to the ciliary membrane. Neurons throughout the mammalian brain possess primary cilia upon which certain G protein-coupled receptors localize. Yet, the precise signaling proteins present on the vast majority of neuronal cilia are unknown. Here, we report that dopamine receptor 1 (D1) localizes to cilia on mouse central neurons, thereby implicating neuronal cilia in dopamine signaling. Interestingly, ciliary localization of D1 is dynamic and the receptor rapidly translocates to and from cilia in response to environmental cues. Notably, the translocation of D1 from cilia requires proteins mutated in the ciliopathy Bardet-Biedl syndrome (BBS) and we find that one of the BBS proteins, Bbs5, specifically interacts with D1.
The acid-sensing ion channels (ASICs) are proton-gated cation channels activated when extracellular pH declines. In rodents, the Accn2 gene encodes transcript variants ASIC1a and ASIC1b, which differ in the first third of the protein and display distinct channel properties. In humans, ACCN2 transcript variant 2 (hVariant 2) is homologous to mouse ASIC1a. In this article, we study two other human ACCN2 transcript variants. Human ACCN2 transcript variant 1 (hVariant 1) is not present in rodents and contains an additional 46 amino acids directly preceding the proposed channel gate. We report that hVariant 1 does not produce proton-gated currents under normal conditions when expressed in heterologous systems. We also describe a third human ACCN2 transcript variant (hVariant 3) that is similar to rodent ASIC1b. hVariant 3 is more abundantly expressed in dorsal root ganglion compared with brain and shows basic channel properties analogous to rodent ASIC1b. Yet, proton-gated currents from hVariant 3 are significantly more permeable to calcium than either hVariant 2 or rodent ASIC1b, which shows negligible calcium permeability. hVariant 3 also displays a small acid-dependent sustained current. Such a sustained current is particularly intriguing as ASIC1b is thought to play a role in sensory transduction in rodents. In human DRG neurons, hVariant 3 could induce sustained calcium influx in response to acidic pH and make a major contribution to acid-dependent sensations, such as pain.The acid-sensing ion channels (ASICs) 4 are a family of proton-gated cation channels expressed in neurons throughout the central and peripheral nervous system (1). There are four ASIC genes (Accn1-4) that produce at least six individual ASIC subunits in rodents (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4). ASIC subunits have a characteristic topology with two transmembrane domains separated by a large cysteine-rich extracellular region (2, 3). Three individual ASIC subunits associate to form functional cation channels that are activated by decreases in extracellular pH (4, 5). ASIC currents are typically transient, inactivate even in the continued presence of acidic pH, and (except for ASIC1a) are not substantially permeable to calcium (6). The specific properties of an ASIC current, such as the pH necessary for activation and the kinetics of inactivation, are defined by the subunit composition of the channel (7). In the central nervous system, the ASIC1a subunit plays an important role (8). Genetic disruption or pharmacological inhibition of ASIC1a affects learning and memory, fear-related behaviors, pain, depression, and seizure duration in rodents (9 -15). ASIC1a also contributes to neuronal damage after cerebral ischemia in mice and mediates neuronal death following prolonged acidosis (16 -19). ASIC1a is thought to play a prominent role in neuronal death because it is uniquely permeable to calcium compared with other ASICs (16,20,21).In rodents, the Accn2 gene encodes both ASIC1a and ASIC1b. ASIC1b is a transcript variant expressed...
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