Ion Channels in the Paraventricular Hypothalamic Nucleus (PVN); Emerging Diversity and Functional Roles

Abstract

The paraventricular nucleus of the hypothalamus (PVN) is critical for the regulation of homeostatic function. Although also important for endocrine regulation, it has been referred to as the “autonomic master controller.” The emerging consensus is that the PVN is a multifunctional nucleus, with autonomic roles including (but not limited to) coordination of cardiovascular, thermoregulatory, metabolic, circadian and stress responses. However, the cellular mechanisms underlying these multifunctional roles remain poorly understood. Neurones from the PVN project to and can alter the function of sympathetic control regions in the medulla and spinal cord. Dysfunction of sympathetic pre-autonomic neurones (typically hyperactivity) is linked to several diseases including hypertension and heart failure and targeting this region with specific pharmacological or biological agents is a promising area of medical research. However, to facilitate future medical exploitation of the PVN, more detailed models of its neuronal control are required; populated by a greater compliment of constituent ion channels. Whilst the cytoarchitecture, projections and neurotransmitters present in the PVN are reasonably well documented, there have been fewer studies on the expression and interplay of ion channels. In this review we bring together an up to date analysis of PVN ion channel studies and discuss how these channels may interact to control, in particular, the activity of the sympathetic system.

Activation of alpha‐1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus

“…The elimination of [Ca 2+ ] i elevation by removing extracellular Ca 2+ or blocking channels with Cd 2+ strongly indicates the involvement of one or more plasma membrane proteins. Both magno‐ and parvocellular neurones express L‐type Ca 2+ channels, and parvocellular neurones express T‐type Ca 2+ channels as well . Non‐neurosecretory parvocellular neurones have much larger T‐type Ca 2+ currents then neurosecretory parvocellular neurones, and these low threshold channels may be responsible for the [Ca 2+ ] i increase that we observe.…”

“…Because our cultures likely contain multiple types of PVN neurones, the differential expression of T‐type currents may also explain why only a subset of neurones increased [Ca 2+ ] i when exposed to NE or PE. In addition, Ca 2+ permeable transient receptor potential cation (TRP) channels and NMDA receptors are also present in the PVN, and may contribute to [Ca 2+ ] i influx upon depolarisation or phosphorylation. Although Cd 2+ is a prototypical voltage‐dependent Ca 2+ channel (VDCC) blocker, it has also been shown to block TRP channels .…”

“…Because our cultures likely contain multiple types of PVN neurones, the differential expression of T-type currents may also explain why only a subset of neurones increased [Ca 2+ ] i when exposed to NE or PE. In addition, Ca 2+ permeable transient receptor potential cation (TRP) channels 55 and NMDA receptors 56 39 In other central neurones, α 1 -AR activation increases action potential discharge and depolarises membranes in the rat medial pontine reticular formation, 66 excites mouse purkinje neurones, 67 induces Ca 2+ oscillations in the anterior pituitary, 52 and increases EPSP frequency and induces membrane depolarisation in the rat sacral autonomic nucleus. 68 (Figure 6; cAMP to PKA 37 ; and even cPLA 2 activation.…”

Emerging Roles of the Membrane Potential: Action Beyond the Action Potential

“…This in turn increases the activation of Ca 2+ -activated K + channels and enables the feedback loop to continue. We were able to simulate this numerically in the case of the PVN neurones ( Feetham et al, 2018 ). We demonstrated that the Ca 2+ elevation appears to be mediated by TRPV4 channels, and that the small-conductance Ca 2+ -activated K + channels (SK channels) mediate a hyperpolarization that both increases intracellular Ca 2+ and decreases their action potential firing frequency ( Feetham et al, 2015b ).…”

Activation of prodynorphin neurons in the dorsomedial hypothalamus inhibits food intake and promotes positive valence

“…1c). Therefore, the distribution of tdTomato-positive neurons in the PVH were assessed according to the subdivisions described in the previous report 21 (Fig. 1e).…”