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Published in Philip Winn, Dictionary of Biological Psychology, 2003
A process of modification of an ACTION POTENTIAL. It can be produced by a slow afterhyperpolarization CURRENT (that is an ION flow that occurs after HYPERPOLARIZATION has been initiated), an effect that involves a calcium (Ca2+) activated potassium (K+) current into the NEURON. The net effect of the afterhyperpolarization current is to reduce the generation of action potentials when neurons are in a state of constant depolarization: in crude terms it is a braking mechanism. It is a process that has been associated with beta ADRENOCEPTORS, which can increase firing in neurons that are already excited.
Altered Calcium Homeostasis in Old Neurons
Published in David R. Riddle, Brain Aging, 2007
Information about age-related changes in the function and activity of the ER Ca2+ stores is rather limited, with an overall view that the size of the caffeinereleasable ER Ca2+ store is reduced by aging, as shown both in granule neurons of the cerebellar slices [94] and in aged acutely dissociated basal forebrain neurons [80], but not in cultured hippocampal neurons [95]. There are several mechanisms that can explain a decrease in the size of the caffeine-sensitive Ca2+ stores, including a decreased efficiency of the reuptake mechanisms through the SERCA pumps or an increased Ca2+ leakage. When investigated directly, in acutely dissociated basal forebrain neurons, aging did not affect the rate of spontaneous depletion (i.e., leakage) but decreased the efficiency of the ER loading [96]. In contrast, in long-term (30 days in vitro) cultured hippocampal neurons, glutamate stimulation activated a sustained Ca2+ response that was inhibited by rynanodine, a blocker of CICR, thus indicating an increased ER Ca2+ leak [95]. It is not clear yet if this increased Ca2+ leak, in effect a sustained CICR, was due to an alteration in the function of the rynanodine receptors or was related to a possible coupling between the L-type VOCCs and the rynanodine Ca2+-release channels [97], similar to the coupling between these types of Ca2+ channels in the muscle and which is known to be affected by the aging process [98]. An interesting observation on the role of intracellular Ca2+ stores in alterations in the normal Ca2+ homeostasis in the aged neurons has been recently reported with respect to the process of hippocampal LTP induction. Release of Ca2+ from the intracellular stores is an important participant in LTP induction for ranges of stimulation near the threshold of induction [99, 100]; but in the aged slices, inhibition of the Ca2+ release from the stores by either SERCA inhibitors or by rynanodine activated, rather than inhibited, LTP [101]. The explanation proposed for this paradoxical effect takes into account another well-established effect of Ca2+ in the aged neurons: activation of a slow afterhyperpolarization (AHP) current [102, 103], which in turn will affect the level of synaptic depolarization required for NMDA receptor and consequent LTP induction. The fact that aging is associated with a decline in LTP and synaptic plasticity [104, 105] might indicate an increase with age of the functional release of Ca2+ from the intracellular stores in these hippocampal neurons.
Approaches for the discovery of drugs that target K Na 1.1 channels in KCNT1-associated epilepsy
Published in Expert Opinion on Drug Discovery, 2022
Barbara Miziak, Stanisław J Czuczwar
Physiologically, ion channels – KNa 1.1 are involved in the establishment and maintenance of the resting membrane potential as well as in the generation of slow afterhyperpolarization. This in turn occurs after bursts of action potentials and serves to reduce subsequent firing [43]. In addition to imaging the structure of ion channels themselves, it is also important to correlate these structures with the functional states of a given protein in vitro. One such technique to study the structure and function of ion channels is lipid nanodiscs using single-particle cryo-EM [67]. Cole et al. [20] used KNa1.1 channel structures, obtained by the Cryo-EM technique, to create an in silico binding model for the KNA1.1 channel inhibitor quinidine.