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All living organisms have the capacity to sense and respond to mechanical stimuli permeating their environment. Mechanosensory signaling constitutes the basis for the senses of touch and hearing and contributes fundamentally to development and homeostasis. Intense genetic, molecular, and elecrophysiological studies in organisms ranging from nematodes to mammals have highlighted members of the DEG/ENaC family of ion channels as strong candidates for the elusive metazoan mechanotransducer. These channels have also been implicated in several important processes including pain sensation, gametogenesis, sodium re-absorption, blood pressure regulation, and learning and memory. In this chapter, we review the evidence linking DEG/ENaC ion channels to mechanotransduction and discuss the emerging conceptual framework for a metazoan mechanosensory apparatus.

From the point of view of sensation, the heart is a curious organ. Sensory neurons innervate it, but we all hope never to be aware of them. The only conscious sensation they cause is pain and the only trigger for this is ischemia-when the heart gets insufficient oxygen. It is a sensation often felt only in the last minute of life. This raises two fundamental questions: (1) what purpose do these neurons serve besides mediating ischemic pain?; (2) what signal activates them? Lactic acid is an obvious candidate for the signal because it is released by muscle whenever there is insufficient oxygen. However, researchers have argued that lactic acid cannot be a trigger for ischemic pain because metabolic acidosis does not cause chest pain even though it can drop pH to levels equivalent to those that occur during myocardial infarction.

For several decades, our attempt to characterize afferent signals from cardiovascular or peripheral sensory nerves has focused on the description of action potentials in single fibers classified according to their thickness, their conduction velocity, or the degree of their myelination.We are now at the point where we need to define the molecular components of the ion channels and associated proteins that are responsible for mechano-chemo transduction, nociception, temperature, and touch sensitivity.

The sensory systems of higher organisms utilize ion channels to transduce sensory stimuli into electrical signals. The sensory channels are either directly activated, such as observed for some mechanically sensitive channels (e.g., in touch), or indirectly activated by chemical components of a transduction pathways, such as observed for phototransduction and other pathways. Independent of these specialized sensory cells, most cells in living organisms have the ability to sense and respond to alterations in local chemical and physical stimuli. In general, the molecular components of these cellular sensors and their transduction pathways are poorly understood.

Progress in understanding the central nervous system (CNS) mechanisms regulating cardiovascular function has long been linked to the neurobiology of cranial primary sensory afferents. Activation of visceral afferents with chemical substances provided seminal evidence that particular afferents even within a single organ (e.g., the heart) or sensory modality (e.g., mechanoreceptors) could have fundamentally different characteristics and evoke unique reflex outcomes. In cardiorespiratory afferent studies, early practitioners deployed a range of sometimes rather exotic exogenous compounds to probe the discharge properties of afferent nerves as well as to evoke reflex responses. These chemicals ranged from neurotransmitters, peptides, prostanoids, cytokines, phenylbiguanide, and veratridine to nicotine. Thus, the pharmacology of primary visceral afferents is intimately interwoven into the fabric of CNS processing and the physiology of autonomic reflexes.

The transient receptor potential (TRP) family of ion channels was first characterized in , where the gene was found to be required for visual transduction in a phospholipase C (PLC) dependent process.

Noxious thermal, mechanical, or chemical stimuli evoke pain through excitation of the peripheral terminals called nociceptors. Many kinds of ionotropic and metabotropic receptors are involved in this process. TRPV1, a capsaicin receptor, is a nociceptor-specific ion channel that serves as the molecular target of capsaicin, having six transmembrane domains with a short hydrophobic stretch between the fifth and sixth transmembrane domains.

TRPV4 was identified as the mammalian homologue of the osmosensory channel protein, OSM-9. This nonselective cation channel is activated by even modest degrees of hypotonic cell swelling. Its expression in the mammalian central nervous system and kidney suggests a role in systemic osmoregulation—a view borne out by detailed balance studies in TRPV4-null mice. Two distinct mechanisms have been described through which TRPV4 may be activated by hypotonicity: one involves the SRC family of nonreceptor protein tyrosine kinases, while the other is mediated via arachidonic acid metabolites.

Endothelial cell (EC) responsiveness to fluid-mechanical shear stress is essential for normal vascular function and may play a role in the localization of early atherosclerotic lesions. Although ECs are known to be exquisitely sensitive to flow, the precise mechanisms by which ECs sense and respond to shear stress remain incompletely understood. The activation of flow-sensitive ion channels is one of the most rapid endothelial responses to shear stress; therefore, these ion channels have been proposed as candidate flow sensors. A central role for flowsensitive ion channels in EC shear sensing is supported by recent data demonstrating that blocking these ion channels profoundly affects downstream endothelial flow signaling.

Oxidant production and regulation is becoming increasingly important in the study of vascular signaling mechanism.Alarge number of studies during the last 50 years have provided evidence that vascular preparations show alterations in contractile function over a wide range of O tensions that are observed in physiological systems. Based on observations that reactive oxygen species were vasoactive and appeared to have distinct signaling mechanisms, itwas suggested that these species could function in vascular O sensing mechanisms that mediated responses to acute changes in pO.