Modulation of ion channels by somatostatin and acetylcholine

Abstract

Somatostatin and muscarinic acetylcholine receptors are similar as far as modulation of voltage-gated Ca 2+ channels and anomalously rectifying K + channels are concerned. Activation of either type of receptors induces inhibition of Ca 2+ channels and activation of anomalous K + channels without depending on intracellular cAMP. Somatostatin appears to act on the same receptor subtype for these two actions since somatostatin receptors are homogenous in pituitary cells (Srikant and Patel, 1982; Tran et al., 1985) where the peptide produces these two effects as well as an inhibition of adenylate cyclase. In the case of muscarinic receptors, however, it remains unclear whether the same subtype of receptors is involved in both inhibition of Ca 2+ channels and activation of K + channels. Activation of muscarinic receptors in hippocampal neurones evidently produces a cAMP-independent suppression of Ca 2+ channel. In cardiac cells, however, muscarinic stimulation does not cause a cAMP-independent suppression of Ca 2+ channels but does activate an anomalous rectifier. These findings do not necessarily mean that the muscarinic receptor involved in the inhibition of Ca 2+ channels in hippocampal neurones is not of m2 type which is assumed to mediate the activation of anomalous K + channels in cardiac cells. There is no evidence that cardiac Ca 2+ channels are identical to hippocampal Ca 2+ channels susceptible to muscarinic inhibition. In addition, a similar argument could be applied to G proteins coupling muscarinic receptors to Ca 2+ channels in neurones and cardiac myocytes. In this regard, it should be noted that activation of GABA B receptors or μ and δ opiate receptors, an event known to inhibit adenylate cyclase activity through a PTX-sensitive Gi protein, also produces both inhibition of Ca 2+ channels and activation of anomalous K channels in a cAMP-independent manner. This close correlation between inhibition of adenylate cyclase activity and cAMP-independent modulation of Ca 2+ and K + channels suggests the possible involvement of m2 subtype in the inhibition of Ca 2+ channels in hippocampal neurones. Circumstantial evidence indicates that anomalous K + channels are directly activated by α subunits of Gi, but not Go, proteins. The α subunit of Go protein seems to mediate inhibition of the Ca 2+ channel, probably in a direct manner. The most striking difference between somatostatin and muscarinic receptors would be their opposite actions on the M channel. All the inhibitory receptors on the M channel, including m1 and m3 receptors, are known to stimulate PI hydrolysis via a PTX-insensitive G protein. However, protein kinase C may not be a principal mediator for the inhibition of M channels, as deduced from studies with protein kinase C inhibitors and activators. On the other hand, facilitation of M channels so far observed is associated only with the somatostatin receptor and β adrenoceptor. Although lipoxygenase metabolites of arachidonic acid were suggested to be second messengers for somatostatin, biochemical findings do not support this notion. As has been proposed for the If channel in cardiac pacemaker cells, M channels might be controlled directly by two different G proteins in an opposite manner. A cation nonselective channel is coupled only with the muscarinic receptor, probably the m4 subtype. A PTX-sensitive G protein mediates this coupling without involving cAMP, cGMP, protein kinase C, or intracellular Ca 2+. Therefore, it is possible that a PTX-sensitive G protein directly activates the muscarinic cation channel. If such is the case, then why don't other receptor agonists activate cation nonselective channels? There may be a limited distribution of cation nonselective channels since similar muscarinic cation channels have been noted only in smooth muscle of the stomach. The main function of somatostatin receptors is inhibition of membrane excitability through suppression of a voltage-gated Ca 2+ channel and activation of an anomalously rectifying K + channel. These effects on Ca 2+ and K + channels may account, at least in part, for relaxation of cardiac muscle and suppression of hormone release from pituitary cells. By contrast, functions of muscarinic receptors are not straightforward. The activation of muscarinic receptors results in relaxation of cardiac myocytes, but in contraction of smooth muscle. At the channel level, muscarinic receptors, as compared with somatostatin receptors, are coupled with more diverse ion channels. Such a wide variety of muscarinic functions may reflect the diversity of muscarinic receptor subtypes and their selective involvement in certain aspects of cellular metabolism such as PI hydrolysis and the inhibition of adenylate cyclase.