ERG inhibitor (University of Michigan/OncoFusion Therapeutics)

The regulation of electrical excitability of anterior pituitary corticotrophs is critical for an appropriate response of the hypothalamic‐pituitary‐adrenal (HPA) axis in the face of diverse physiological challenges in health and disease. However ion channels that control corticotroph excitability remain poorly characterised. Members of the mammalian ether‐à‐go‐go (EAG) channel family are voltage‐gated potassium channels with diverse functions in the endocrine, cardiovascular and nervous systems. Expression of Kcnh2 mRNA, which encodes for the Eag‐related potassium channel Erg1, is enriched in the anterior pituitary although its functional role is poorly understood in native anterior pituitary cells. We reveal that Kcnh2 is the major Eag‐channel family member mRNA expressed in male and female murine corticotrophs. Patch clamp electrophysiological analysis revealed corticotrophs exhibit robust Erg‐like currents that are inhibited by the selective Erg‐inhibitor E4031 but are not regulated by the major hypothalamic secretagogues, corticotrophin releasing hormone (CRH) or arginine vasopressin (AVP), that increase corticotroph excitability. Pharmacological inhibition of Erg currents had no effect on spontaneous electrical excitability in corticotrophs. Rather, paradoxically, Erg currents were important for supporting CRH‐induced bursting, similar to the role of large‐conductance calcium‐ and voltage‐activated potassium (BK) channels, providing a level of redundancy to control bursting. Indeed mathematical modelling revealed that in the absence of BK channels CRH‐induced bursting can be supported in thepresence of Erg current. We thus reveal a novel role for Erg‐like channels in controlling CRH‐induced bursting in murine anterior pituitary corticotrophs that is likely to be an important determinant of HPA axis regulation in health and disease. image

Voltage‐gated ether‐à‐go‐go‐related (Erg) potassium channels are key determinants of cellular excitability; however their functional role in native anterior pituitary cells remains poorly understood.Male and female murine corticotrophs predominantly express Kcnh2 (Erg1) mRNA, and electrophysiological recordings reveal functional Erg‐like potassium currents sensitive to the Erg inhibitor E4031.Erg currents do not control the basal electrical excitability of corticotrophs.We reveal a novel role for Erg currents in supporting electrical bursting in corticotrophs induced by the hypothalamic secretagogue, corticotrophin releasing hormone (CRH).Bursting in corticotrophs can be supported by both Erg and BK channels revealing a level of redundancy to the CRH response that will be critical for understanding the role of Erg channels in control of the stress axis in health and disease.