Signal transduction pathways and gating mechanisms of native TRP-like cation channels in vascular myocytes

Abstract

Activation of Ca2+-permeable non-selective cation channels produces an increase in excitability of vascular smooth muscle cells which has an important role in vasoconstriction. These channels are activated by various physiological stimuli including vasoconstrictor agents such as noradrenaline, depletion of internal Ca2+ stores and cell stretching. In addition cation channels have been shown to be constitutively active and these channels are thought to contribute to resting membrane conductance and basal Ca2+ influx in vascular myocytes. Recent evidence has suggested that transient receptor potential (TRP) proteins represent strong candidates for these channels in the vasculature. This review discusses proposed signal transduction pathways and gating mechanisms which link physiological stimuli to opening of cation channels in vascular myocytes. It is apparent that G-protein-coupled pathways linked to stimulation of phospholipase activity have a profound effect on regulating channel activity and that generation of diacylglycerol (DAG) is a central event in these signalling cascades with this triglyceride having a pivotal role in gating cation channels via both PKC-independent and -dependent mechanisms. Moreover phosphorylation processes produced by stimulation of protein kinases have been proposed to have an important role in regulating cation channel activity.

Figure 1. Regulation of ROCs by signal transduction pathways in rabbit portal vein myocytes

Stimulation of G-protein-coupled receptors activates ROCs through the classical PI system, which generates DAG leading to channel opening via a PKC-independent mechanism. Activation of tyrosine kinase receptors also activates channel opening. Note that Ins(1,4,5)P₃, pp60^c-src and a phosphorylation step involving a CaM kinase II/MLCK-like molecule have all been shown to be involved in activating ROCs.

Figure 2. Activity of CCCs is regulated by parallel signal transduction pathways in rabbit ear artery myocytes

Spontaneously active G_αi/o proteins activate CCCs by stimulating PC-PLD, leading to hydrolysis of PC and generation of DAG via phosphatidic acid, which opens channels by a PKC-independent mechanism. In parallel to this excitatory pathway spontaneously active G_αq/α11 proteins inhibit CCC activity through a PKC-dependent mechanism involving stimulation of the classical PI biochemical cascade system.

Figure 3. Activation mechanisms of SOCs in vascular myocytes

The activation mechanisms of SOCs in aortic and portal vein myocytes are shown. In aortic myocytes SOCs are activated by LPLs produced by stimulation of iPLA₂ with this phospholipase regulated by release of CIF from depleted internal Ca²⁺ stores. In portal vein SOCs are activated by a store-dependent process involving activation of PKC via an unknown pathway (denoted by dashed line) and by a store-independent pathway involving G-protein-coupled receptors which are also linked to activation of PKC.