G proteins as regulators of ion channel function

Abstract

Virtually unknown just a decade ago, GTP-binding proteins (G proteins) have become a major focus of current research. This family of closely related proteins transduce extracellular signals (such as hormones, neurotransmitters and sensory stimuli) into effector responses 1,2 . It is now evident that ion channel permeability is one such effector response. In fact, the striking increase in the frequency of reports that demonstrate G protein-regulated ion channel function suggests that channels whose permeability mechanism can be altered by a G protein-mediated process may be more the rule than the exception. It is well-known that the cAMP-dependent modulation of ion channels is under the control of G proteins that regulate adenylate cyclase activity 3,4 . However recent studies demonstrate that G proteins also transduce agonist-induced changes in channel activity that do not involve adenylate cyclase. It is on this aspect of G protein signal transduction that this review will focus.Much of our information on the mechanisms underlying G protein function comes from research on G s , the regulatory protein mediating hormonal stimulation of adenylate cyclase. According to one presently accepted model (for review see Ref. 5), G s , in the non-activated state, exists as a heterotrimer of α-, β-and γ-subunits with GDP bound on the α-subunit (G-GDP). The interaction of agonist, receptor, and G-GDP accelerates the exchange of GTP for bound GDP. Binding of GTP by the α-subunit stimulates both the dissociation of G-GTP from the agonist-receptor complex, and the dissociation of the G protein itself into α-GTP (the active subunit with GTPase activity) and βγ (the regulatory dimer). Via a mechanism that remains to be identified, α-GTP promotes an increase in adenylate cyclase activity. The action of α-GTP is terminated through the α-subunit-mediated hydrolysis of GTP followed by reassociation of the α-subunit with free βγ to reform the inactive G-GDP. The agonistinduced activation of a G protein and its deactivation through hydrolysis of GTP is illustrated schematically by the cycle in Fig. 1. This general scheme of events has been postulated to underlie the mechanism of action of other, more recently discovered G proteins (G i and G o ) 6-8 , although the receptors and, in some cases, the effector enzymes involved are different. In addition to its inhibitory role in the regulation of adenylate cyclase, a G i -like protein may, for example, control the activity of other second messenger-generating enzymes such as phospholipase C or phospholipase A 2 9-12 . Similarly, it has been thought that G o , a regulatory protein found in abundance in neural tissue (~1% of total protein), might also be linked to enzyme effectors other than adenylate cyclase but, until recently, the α-subunit of G o has had no demonstrable physiological function. A recent paper by Hescheler et al. 13 indicates that α o may play a pivotal role in regulating Ca 2+ channel function in neurons. Furthermore, the recently reported co-localization of α o i...

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