Stimuli, mechanical, cellular

The ability to reduce stimulus-response mechanisms to single mono tonic functions allows relative cellular response to yield receptor-specific drug parameters. 

Previously, pharmacologists were constrained to the prewired sensitivity of isolated tissues for agonist study. As discussed in Chapter 2, different tissues possess different densities of receptor, different receptor co-proteins in the membranes, and different efficiencies of stimulus-response mechanisms. Judicious choice of tissue type could yield uniquely useful pharmacologic systems (i.e., sensitive screening tissues). However, before the availability of recombinant systems these choices were limited. With the ability to express different densities of human target proteins such as receptors has come a transformation in drug discovery. Recombinant cellular systems can now... 

The identity of factors released from damaged neurons to signal microglial cell activation may depend upon which type of neural cell is damaged, neuron versus glial, and on the the toxin or stimulus, glutamate versus /1-amyloid versus a-synuclein, and the nature of cellular death, apoptosis versus necrosis. Similarly, the molecular mechanisms and internal and external factors that modulate the dynamic aspects of acute and chronic inflammation in cell injury mediated by glutamate remain unclear. It also remains unclear to what extent inflammation is beneficial... 

Mechanoreception is the term used to describe the process that transmits the informational content of an extracellular mechanical stimulus to a receptor cell. Mechanotransduction is the term used to describe the process that transforms the mechanical stimulus content into an intra-cellular signal. The term mechanosensory is employed to mean both mechanoreception and mechanotransduction. Additional processes of inter-cellular transmission of transduced signals are required at tissue, organ and organismal structural levels. The mechanosensing process(es) of a cell enables it to sense the presence of, and to respond to, extrinsic physical loadings. This property is widespread in uni- and multicellular animals [54, 101, 53, 74, 73, 36] plants [201, 65] and bacteria [152], Tissue sensibility is a property of a connected set of cells and it is accomplished by the intracellular processes of mechanoreception and mechanotransduction. 

An enhancement of ATPase action comes through the phosphorylation of myosin light chains (MW 18,000). The phosphorylation is achieved because the high cellular [Ca2+] activates myosin kinase, an enzyme that contains calmodulin, a Ca2+-binding subunit. Phosphorylation of myosin is absolutely required for smooth muscle contraction, though not for the contraction of skeletal or cardiac muscle, because smooth muscle has no troponin. Thus, whereas contraction and relaxation in skeletal and cardiac muscle are achieved principally via the action of Ca2+ on troponin, in smooth muscle they must depend solely on the Ca2+-dependent phosphorylation of myosin. In skeletal and cardiac muscle, once the stimulus to the sarcolemma is removed, [Ca2+] in sarcoplasm drops rapidly back to 10 7 or 10 8 M via various Ca2+ pump mechanisms present in the sarcoplasmic reticulum, and tropomyosin can once again interfere with the myosin-actin interaction. 

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