(DOWNLOAD) "Dynamic Modulation of Acid-Sensing Ion Channels" by Thomas Walworth Sherwood " Book PDF Kindle ePub Free
eBook details
- Title: Dynamic Modulation of Acid-Sensing Ion Channels
- Author : Thomas Walworth Sherwood
- Release Date : January 21, 2013
- Genre: Medical,Books,Professional & Technical,
- Pages : * pages
- Size : 20697 KB
Description
Acidification of tissue pH has long been recognized as a component of the injury process for many diseases and injuries that affect the brain and spinal cord. Acute injuries like stroke and trauma induce severe long-lasting acidosis in the brain, and low tissue pH has been observed in brain lesions associated with neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. How exactly low extracellular pH contributes to the loss of neurons associated with these injuries remains an unanswered question. Recently, a family of ion channels was discovered that respond directly to extracellular free protons (low extracellular pH). This family, known as the Acid-Sensing Ion Channels (ASICs) mediates acid-induced death of neurons, but little is known about how ASICs activate during pathological acidosis, and what endogenous factors control their activity.I began my thesis studying the ASIC1a and ASIC2a channels specifically, in an effort to determine how ASICs are gated by protons, and how extracellular calcium regulates their activity. This work lead to the discovery that two regions of the ASIC protein control high-affinity proton sensing in ASIC1a. I also discovered a novel area of the human ASIC1a protein that controls calcium-dependent modulation of channel activation. These results allow us to better understand how ASICs respond to both protons and calcium, and may help to develop treatments which prevent ASIC-mediated cell death during injury conditions.Normally, ASICs require acute rapid decreases in extracellular pH to activate. Slow incremental decreases in pH, which are expected to occur during brain injury, cause ASICs to desensitize to acid, and limit channel activity. Yet, ASICs clearly contribute to neuronal death. To gain a better understanding of how ASIC desensitization occurs, and what impact it has on acid-induced death, I researched areas of the ASIC protein that control this form of channel desensitization. This work lead to the discovery of a protein region that regulates desensitization of ASIC1a. I also determined that desensitizing ASICs, by gradually reducing pH, can protect neurons from prolonged acidosis. Interestingly, I discovered that several specific classes of endogenous neuropeptides prevent ASIC desensitization, allowing for much greater channel activation. I found these peptides also enhance ASIC-mediated cell death. This has important implications for acid-induced death in vivo, suggesting that induction of ASIC desensitization could prevent acid-dependent brain damage. It also demonstrates that certain neuropeptides enhance cell death by stopping ASIC desensitization.There are multiple ASIC subunits expressed in the brain. Only some of these ASICs are known to contribute acid-evoked current in neurons. I investigated the role of ASIC2b, a subunit with unknown function, in proton-gated current of central neurons. I found that ASIC2b pairs with ASIC1a to form functional channels with some distinct properties. I found that ASIC2b/1a channels are present in many hippocampal neurons. Further, I found that ASIC2b/1a is calcium permeable, and contributes to acid-induced neuronal death. These experiments are the first to describe novel characteristics of ASIC2b/1a channels, and offer a mechanism for ASIC2-dependent toxicity in central neurons.Taken together, this work has helped to establish how ASICs activate in different extracellular conditions, and what factors impact their activity. I have discovered previously unknown protein domains in ASICs that contribute to their function. I also describe, for the first time, a heteromeric ASIC channel present in hippocampal neurons that contributes to acid-induced neuronal death. I discovered a novel aspect of neuropeptide modulation of ASICs, and describe how this modulation influences acid-dependent cell death. This work has significant implications for understanding how acid contributes to brain injury, and how ASICs can be utilized as a target to limit acid-dependent cell death.
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