Accepted

Electrical signaling was a dramatic development in evolution, allowing complex single-cell organisms like Paramecium to coordinate movement and early metazoans like worms and jellyfish to send regulatory signals rapidly over increasing distances. But how are electrical signals generated in biology? In fact, voltage-gated sodium channels conduct sodium currents that initiate electrical signals in all kingdoms of life, from bacteria to man. They are responsible for generating the action potential in vertebrate nerve and muscle, neuroendocrine cells, and other cell types. Because of the high level of conservation of their core structure, it is likely that their fundamental mechanisms of action are conserved as well. Here we describe the complete cycle of conformational changes that a bacterial sodium channel undergoes as it transitions from resting to activated/open and inactivated/closed states, based on high-resolution structural studies of a single sodium channel. We further relate this conformational cycle of the ancestral sodium channel to the function of its vertebrate orthologs. The strong conservation of amino acid sequence and three-dimensional structure suggests that this model, at a fundamental level, is relevant for both prokaryotic and eukaryotic sodium channels, as well as voltage-gated calcium and potassium channels.

Interest in deciphering the fundamental mechanisms and processes of the human mind represents a central driving force in modern neuroscience research. Activities in support of this goal rely on advanced methodologies and engineering systems that are capable of interrogating and stimulating neural pathways, from single cells in small networks to interconnections that span the entire brain. Recent research establishes the foundations for a broad range of creative neurotechnologies that enable unique modes of operation in this context. This review focuses on those systems with proven utility in animal model studies and with levels of technical maturity that suggest a potential for broad deployment to the neuroscience community in the relatively near future. We include a brief summary of existing and emerging neuroscience techniques, as background for a primary focus on device technologies that address associated opportunities in electrical, optical and microfluidic neural interfaces, some with multimodal capabilities. Examples of the use of these technologies in recent neuroscience studies illustrate their practical value. The vibrancy of the engineering science associated with these platforms, the interdisciplinary nature of this field of research and its relevance to grand challenges in the treatment of neurological disorders motivate continued growth of this area of study.

Transient receptor potential melastatin 8 (TRPM8) channels play a central role in the detection of environmental cold temperatures in the somatosensory system. TRPM8 is found in a subset of unmyelinated (C-type) afferents located in the dorsal root (DRG) and trigeminal ganglion (TG). Cold hypersensitivity is a common symptom of neuropathic pain conditions caused by cancer therapy, spinal cord injury, viral infection, multiple sclerosis, diabetes, or withdrawal symptoms associated with chronic morphine treatment. Therefore, TRPM8 has received great attention as a therapeutic target. However, as the activity of TRPM8 is unique in sensing cool temperature as well as warming, it is critical to understand the signaling transduction pathways that control modality-specific activity of TRPM8 in healthy versus pathological settings. This review summarizes recent advances in our understanding of the mechanisms involved in the regulation of the TRPM8 activity.