Physiological integration of GPCR signalling cascades

This chapter has reviewed some basic concepts regarding the interactions that occur between seven-transmembrane receptors and ion-selective channels. Yet how do these pathways combine to control the patterns of excitability that underlie neuronal processing in the brain or the cardiac output of the heart? In this respect, a particularly fascinating aspect of receptor-mediated activation of ion channels lies in the range of combinatorial outputs that can be generated by the simultaneous stimulation of different receptors within the same cell. Numerous cells in the central nervous system are responsive to a large assortment of neuro-transmitters that act upon G protein-linked receptors, many of which go on to modulate ion channel function. In several cases, these receptors converge upon common G proteins to initiate overlapping pathways, whereas in other instances the pathways diverge to generate independent signals. The large array of intracellular proteins that are affected by these signals allows for modulation at nearly all stages of the response (Chapters 5 and 7). Receptor subtype diversity adds yet another level of control (Chapters in Parts 2, 3, and 4)—cells respond differently to external signals depending not only on which agonists are present, but also on the types of receptors that the agonists can bind. Perhaps it is this enormous capacity for intervention at multiple steps of the signalling pathway that has made G protein-coupled signalling cascades the systems of choice for most neuroactive transmitters. In turn, understanding the crucial molecular mechanisms involved in physiological and pathophysiological functions remains an elusive challenge despite many years of ongoing investigation.

Taking the brain as a test case the metabotropic effects of several neurotransmitters have been most extensively studied in cells of the cerebral cortex and thalamus. These structures are densely innervated by projection fibres that originate in various brainstem nuclei and project diffusely across different areas of the brain. The addition of acetylcholine to many neocortical pyramidal cells causes a considerable reduction in spike-frequency adaptation, the gradual decrease in firing rate that normally follows a train of action potentials (Madison etal. 1987; McCormick and Williamson 1989). This effect is due in part to the inhibition of a Ca2+-activated potassium current (Iahp) which activates in response to calcium influx and prevents these cells from reaching their firing thresholds (Andrade and Nicoll 1987). The reduction in Iahp thus enhances the effects of subsequent excitatory inputs and causes these cells to become more active. Acetylcholine also inhibits at least two other types of potassium currents in a variety of neuronal cells including the voltage-activated M-current (Im) as well as a resting (leak) potassium conductance (Halliwell 1986; McCormick 1992). In all cases, decreases in these potassium currents gradually shift the transmembrane potential towards more positive, depolarized values and thereby facilitate the activation of voltage-sensitive channels that are open in this range.

Many thalamic neurons receive similar modulatory inputs from cells that originate in the brainstem. Projection fibres that emanate from cell bodies in the locus coeruleus provide noradrenergic innervation to various thalamic nuclei where they increase the excitability of cells in areas such as the lateral geniculate nucleus (LGN) and the nucleus reticularis (Rogawski and Aghajanian 1980; McCormick and Prince 1988). In thalamocortical relay cells, such changes in electrical responsiveness are correlated with different states of wakefulness and attention, and they also influence many aspects of sensory processing in the cortex (McCormick 1989; Swadlow and Gusev 2001). The modulation of membrane excitability in the brain is particularly important at excitatory synapses, where changes in the patterns of synaptic activity combine with changes in synaptic strength to affect the storage of new information during learning, or the reinforcement of synaptic connections during development (Bear and Malenka 1994). Future research should seek to find out more about how individual components of GPCR cascades such as those illustrated above collectively interact to modify membrane excitability and physiological/pathophysiological processes.

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