Direct regulation of ion channels

Direct G protein modulation of ion channels refers to instances in which G protein subunits physically interact with discrete regions of a channel complex to cause changes in the probabilities of opening or closing. Accordingly, changes in channel activity will generally occur in the absence of cytosolic second messengers and are mostly independent of other receptor-activated enzymes. Before considering in detail the events involved in direct G protein gating of ion channels, it is worthwhile to review certain criteria that should be met in order to suggest a direct interaction between these two proteins.

1. The activity of the channel is reversibly altered by the activation of a suitable G proteincoupled receptor, and this regulation is dependent on GTP.

2. Poorly-hydrolyzable GTP analogues such as GTP-y-S or guanylyl-imidodiphosphate (GMP-PNP) promote similar changes in channel activity that are independent of receptor activation.

3. The addition of purified and active G protein subunits to the channel is sufficient to trigger changes in channel activity.

4. A physical association between G proteins and channel subunits can be demonstrated within the confines of an intact cell.

Although the fulfillment of all the above criteria is strongly suggestive of a direct interaction between G proteins and ion channels, they do not constitute ultimate proof that this reciprocal interaction alone is what underlies the observed changes in channel behaviour. The third point illustrates the delicate nature of this issue. Due to the heterogeneous composition of the plasma membrane surrounding the channel, the question remains as to whether purified G protein subunits directly bind to distinct regions of the ion channel to control gating, or whether these proteins simply facilitate the interaction of the channel with surrounding lipids or other membrane-anchored co-factors. In such instances, the direct binding of G proteins to the channel might still be necessary to support and sustain these interactions. Recent evidence suggests that G protein subunits may very well act in concert with other regulatory factors to modify channel activity (see Huang et al. 1998;

Sui et al. 1998). Nonetheless, the continuous presence of the relevant G protein subunit, in its active form, must remain an absolute requirement for maintaining the observed changes in channel behaviour. Furthermore, direct G protein regulation implies that any changes in channel activity cannot proceed in the presence of other co-factors alone.

Direct modulation represents the simplest mechanism by which ion channel activity can be influenced through activated receptors, yet it offers several distinct advantages that are well suited to the needs of many different cells. In contrast to second messenger pathways which seem to favour prolonged, amplified responses, direct modes provide effective ways of narrowing down the pool of potential effector targets. Furthermore, direct gating interactions can greatly help to minimize temporal constraints that are imposed by indirect processes involving several intermediate steps. This form of control is thus advantageous in cases where incoming signals are received at high frequencies and must be rapidly processed.

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