Integrin-KCNB1 potassium channel complexes regulate neocortical neuronal development and are implicated in epilepsy.

Potassium (K+) channels are robustly expressed during prenatal brain development, including in progenitor cells and migrating neurons, but their function is poorly understood. Here, we investigate the role of voltage-gated K+ channel KCNB1 (Kv2.1) in neocortical development. Neuronal migration of glutamatergic neurons was impaired in the neocortices of KCNB1 null mice. Migratory defects persisted into the adult brains, along with disrupted morphology and synaptic connectivity. Mice developed seizure phenotype, anxiety, and compulsive behavior. To determine whether defective KCNB1 can give rise to developmental channelopathy, we constructed Knock In (KI) mice, harboring the gene variant Kcnb1R312H (R312H mice) found in children with developmental and epileptic encephalopathies (DEEs). The R312H mice exhibited a similar phenotype to the null mice. Wild type (WT) and R312H KCNB1 channels made complexes with integrins α5ß5 (Integrin_K+ channel_Complexes, IKCs), whose biochemical signaling was impaired in R312H brains. Treatment with Angiotensin II in vitro, an agonist of Focal Adhesion kinase, a key component of IKC signaling machinery, corrected the neuronal abnormalities. Thus, a genetic mutation in a K+ channel induces severe neuromorphological abnormalities through non-conducting mechanisms, that can be rescued by pharmacological intervention. This underscores a previously unknown role of IKCs as key players in neuronal development, and implicate developmental channelopathies in the etiology of DEEs.

Non-conducting functions of ion channels: The case of integrin-ion channel complexes.

Started as an academic curiosity more than two decades ago, the idea that ion channels can regulate cellular processes in ways that do not depend on their conducting properties (non-ionic functions) gained traction and is now a flourishing area of research. Channels can regulate physiological processes including actin cytoskeletal remodeling, cell motility, excitation-contraction coupling, non-associative learning and embryogenesis, just to mention some, through non-ionic functions. When defective, non-ionic functions can give rise to channelopathies involved in cancer, neurodegenerative disease and brain trauma. Ion channels exert their non-ionic functions through a variety of mechanisms that range from physical coupling with other proteins, to possessing enzymatic activity, to assembling with signaling molecules. In this article, we take stock of the field and review recent findings. The concept that emerges, is that one of the most common ways through which channels acquire non-ionic attributes, is by assembling with integrins. These integrin-channel complexes exhibit broad genotypic and phenotypic heterogeneity and reveal a pleiotropic nature, as they appear to be capable of influencing both physiological and pathological processes.

Antagonistic roles of Ras-MAPK and Akt signaling in integrin-K+ channel complex-mediated cellular apoptosis.

Complexes formed with α5-integrins and the voltage-gated potassium (K+ ) channel KCNB1 (Kv2.1), known as IKCs, transduce the electrical activity at the plasma membrane into biochemical events that impinge on cytoskeletal remodeling, cell differentiation, and migration. However, when cells are subject to stress of oxidative nature IKCs turn toxic and cause inflammation and death. Here, biochemical, pharmacological, and cell viability evidence demonstrates that in response to oxidative insults, IKCs activate an apoptotic Mitogen-activated protein kinase/extracellular signal-regulated kinase (Ras-MAPK) signaling pathway. Simultaneously, wild-type (WT) KCNB1 channels sequester protein kinase B (Akt) causing dephosphorylation of BCL2-associated agonist of cell death (BAD), a major sentinel of apoptosis progression. In contrast, IKCs formed with C73A KCNB1 variant that does not induce apoptosis (IKCC73A ), do not sequester Akt and thus are able to engage cell survival mechanisms. Taken together, these data suggest that apoptotic and survival forces co-exist in IKCs. Integrins send death signals through Ras-MAPK and KCNB1 channels simultaneously sabotage survival mechanisms. Thus, the combined action of integrins and KCNB1 channels advances life or death.