Whilst the phenomenon of an electrical resting membrane potential (RMP) is a central tenet of biology, it is nearly always discussed as a phenomenon that facilitates the propagation of action potentials in excitable tissue, muscle, and nerve. However, as ion channel research shifts beyond these tissues, it became clear that the RMP is a feature of virtually all cells studied. The RMP is maintained by the cell’s compliment of ion channels. Transcriptome sequencing is increasingly revealing that equally rich compliments of ion channels exist in both excitable and non-excitable tissue. In this review, we discuss a range of critical roles that the RMP has in a variety of cell types beyond the action potential. Whereas most biologists would perceive that the RMP is primarily about excitability, the data show that in fact excitability is only a small part of it. Emerging evidence show that a dynamic membrane potential is critical for many other processes including cell cycle, cell-volume control, proliferation, muscle contraction (even in the absence of an action potential), and wound healing. Modulation of the RMP is therefore a potential target for many new drugs targeting a range of diseases and biological functions from cancer through to wound healing and is likely to be key to the development of successful stem cell therapies.

Variation in the time interval between consecutive R wave peaks of the QRS complex has long been recognised. Measurement of this RR interval is used to derive heart rate variability. Heart rate variability is thought to reflect modulation of automaticity of the sinus node by the sympathetic and parasympathetic components of the autonomic nervous system. The clinical application of heart rate variability in determining prognosis post myocardial infarction and the risk of sudden cardiac death is well recognised. More recently, analysis of heart rate variability has found utility in predicting foetal deterioration, deterioration due to sepsis and impending multiorgan dysfunction syndrome in critically unwell adults. Moreover, reductions in heart rate variability have been associated with increased mortality in patients admitted to the intensive care unit. It is hypothesised that heart rate variability reflects and quantifies the neural regulation of organ systems such as the cardiovascular and respiratory systems. In disease states, it is thought that there is an ‘uncoupling’ of organ systems, leading to alterations in ‘inter-organ communication’ and a clinically detectable reduction in heart rate variability. Despite the increasing evidence of the utility of measuring heart rate variability, there remains debate as to the methodology that best represents clinically relevant outcomes. With continuing advances in technology, our understanding of the physiology responsible for heart rate variability evolves. In this article, we review the current understanding of the physiological basis of heart rate variability and the methods available for its measurement. Finally, we review the emerging use of heart rate variability analysis in intensive care medicine and conditions in which heart rate variability has shown promise as a potential physiomarker of disease.

The vasoconstrictor angiotensin II (Ang II) acts at G(q/11)-coupled receptors to suppress ATP-sensitive potassium (K(ATP)) channel activity via activation of protein kinase C (PKC). The aim of this study was to determine the PKC isoforms involved in the Ang II-induced inhibition of aortic K(ATP) channel activity and to investigate potential mechanisms by which these isoforms specifically target these ion channels. We show that the inhibitory effect of Ang II on pinacidil-evoked whole-cell rat aortic K(ATP) currents persists in the presence of Gö6976, an inhibitor of the conventional PKC isoforms, but is abolished by intracellular dialysis of a selective PKCepsilon translocation inhibitor peptide. This suggests that PKC-dependent inhibition of aortic K(ATP) channels by Ang II arises exclusively from the activation and translocation of PKCepsilon. Using discontinuous sucrose density gradients and Western blot analysis, we show that Ang II induces the translocation of PKCepsilon to cholesterol-enriched rat aortic smooth muscle membrane fractions containing both caveolin, a protein found exclusively in caveolae, and Kir6.1, the pore-forming subunit of the vascular K(ATP) channel. Immunogold electron microscopy of rat aortic smooth muscle plasma membrane sheets confirms both the presence of Kir6.1 in morphologically identifiable regions of the membrane rich in caveolin and Ang II-evoked migration of PKCepsilon to these membrane compartments. Ang II induces the recruitment of the novel PKC isoform, PKCepsilon, to arterial smooth muscle caveolae. This translocation allows PKCepsilon access to K(ATP) channels compartmentalized within these specialized membrane microdomains and highlights a potential role for caveolae in targeting PKC isozymes to an ion channel effector.

Chondrocytes are the resident cells of articular cartilage and are responsible for synthesizing a range of collagenous and non-collagenous extracellular matrix macromolecules. Whilst chondrocytes exist at low densities in the tissue (1–10% of the total tissue volume in mature cartilage) they are extremely active cells and are capable of responding to a range of mechanical and biochemical stimuli. These responses are necessary for the maintenance of viable cartilage and may be compromised in inflammatory diseases such as arthritis. Although chondrocytes are non-excitable cells their plasma membrane contains a rich complement of ion channels. This diverse channelome appears to be as complex as one might expect to find in excitable cells although, in the case of chondrocytes, their functions are far less well understood. The ion channels so far identified in chondrocytes include potassium channels (K_ATP, BK, K_v, and SK), sodium channels (epithelial sodium channels, voltage activated sodium channels), transient receptor potential calcium or non-selective cation channels and chloride channels. In this review we describe this emerging channelome and discuss the possible functions of a range of chondrocyte ion channels.