Post-synaptic density protein 95 (PSD95) is a key component of the complex signalling hierarchy in post-synaptic neuronal membranes. In neurones it is highly abundant and combines with an array of molecules including G-protein-coupled receptors, NO synthase, guanine nucleotide exchange factors, tyrosine kinases, anchoring proteins and motor proteins through separate PDZ, Src homology and guanylate kinase-like domains (Kim & Sheng, 2004). This role as a multi-factorial scaffold, integrating a myriad of signals, is fundamental for effective neurotransmission and the synaptic plasticity inherent to memory and learning. In fact it could be said that this protein Cassanova, intimate and promiscuous, defines neuronal activity with its removal, leading to aberrant neuronal transmission. But what is in a name? In a recent issue of The Journal of Physiology, Joseph and colleagues (2011) have now shown that PSD95 should also be considered a key regulator of cerebral artery contractility. This extremely diligent work combining isobaric myography, single cell electrophysiology, membrane potential recording and molecular interference established that the effective function of Kv1 channels, a crucial determinant of the membrane potential in these cell (Albarwani et al. 2003; Chen et al. 2006), was abrogated when PSD95 was disabled. Moreover, this level of control seemed to be fine-tuned for the Kv1.2 α subunit and not the Kv1.5 protein that lacks the PDZ recognition domain. This study ushers in a new dawn for smooth muscle cells. It has been understood for many years that some ion channels coalesce into lipid rafts along with other signalling proteins (Dart, 2010) and should not be perceived simply as pores diffusely sprinkled throughout the membrane. In addition, many vascular smooth muscle cells, including cerebral myocytes, exhibit spatial localisation of the plasmalemmal and sarcolemmal membranes resulting in co-ordinated activation of ion channels (e.g. Jaggar et al. 1998). Moreover, it is well known that no ion channel is an island and the biophysical, regulatory and pharmacological properties are dictated by association with an array of auxillary proteins. What Joseph and colleagues have identified is that vascular smooth muscle cells may also experience the type of protein clustering and spatial organisation that cells with accepted polarity experience. Thus, PSD95 knockout altered the diameter of rat cerebral arteries and reduced membrane currents. More importantly, it abrogated the effects on tissue and membrane currents of the Kv1 blocker Psora, suggesting a selectivity of effect. Hence, disabling a scaffolding protein attenuated the functional impact of Kv1 channels. With any landmark discovery there are more questions and the same exists for the Joseph et al. work. For instance, cerebral arteries also express two other voltage-dependent K+ channels that are important for regulating vessel diameter, namely Kv2 and Kv7 (Zhong et al. 2010a,b). Logically, the Joseph et al. study leads us to ask whether PSD95 interacts and co-ordinates these channels. If so, does the scaffold bring all three Kv channels into a tightly clustered group, increasing repolarisation efficiency or does it allow the separate channels to maintain their distance? At this point it is worth noting that PSD95 is involved with the recruitment of Kv1.4 and Kv4.2 to lipid rafts in cardiomyocytes (Dart, 2010). In addition, Kv1 channels are not just expressed in cerebral myocytes, leading the reader to wonder whether PSD95 is a global regulator of vascular Kv channels or is a preserve of the cerebral vasculature. Finally, the authors themselves postulate that PSD95 may be altered in cardiovascular disease and therefore represents a novel therapeutic target. The fact that a protein known to co-ordinate receptors, ion channels, enzymes and motor proteins is present in cerebral smooth muscle suggests that localised signal complexes may be present. As our understanding of plasmalemmal ion channels, receptors, contractile proteins and structural filaments becomes greater, our view of smooth muscle cells becomes ever more complicated. Having a master co-ordinator on board would improve hierarchical signalling so that the slow creep of hypertension and other vascular diseases may reflect a general loss of co-ordination as the scaffolding is removed. Future experiments will reveal whether PSD95 has as profound an effect in vascular smooth muscle cells as it does in neurones.
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Open Access
Apr 1, 2014
Huayi Wang + 7
