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Recently calcium homeostasis modulators (CALHMs) are identified as ATP release channels play crucial role in functioning of neurons including gustatory signaling and neuronal excitability. Pathologies of Alzheimer's disease and depression have been associated with the dysfunction of CALHMs. Recently, CALHMs has been emerged as an important therapeutic research particularly in neurobiological studies. CALHM1 is most extensively studied among CALHMs and is an ATP and ion channel that is activated by membrane depolarization or removal of extracellular Ca 2+ . Despite the emerged role of CALHM5 shown by an recently assembled data; however, the neuronal function remains obscure until the first Cryo-EM structure of CALHM5 was recently solved by various research group which acts as a template to study the hidden functional properties of the CALHM5 protein based on structure function mechanism. It provides insight in some of the different pathophysiological roles. CALHM5 structure showed an abnormally large pore channel structure assembled as an undecamer with four transmembrane helices (TM1-TM4), an N-terminal helix (NTH), an extracellular loop region and an intracellular C-terminal domain (CTD) that consists of three α-helices CH1-3. The TM1 and NTH were always poorly defined among all CALHMs; however, these regions were well defined in CALHM5 channel structure. In this context, this review will provide insight in structure, function and mechanism to understand its significant role in pathological diseases particularly in Alzheimer's disease. Moreover, it focuses on CALHM5 structure and recent associated properties based on Cryo-EM research., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pannexins, large non-gap junction super family exists in vertebrates, play multiple roles in different cellular functions through their ATP release. Panx1-mediated adenosine 5'-triphosphate (ATP) release plays a vital role in physiological and pathophysiological conditions and is known major extracellular molecule in purinergic signaling. To modulate their function in vivo, a proper regulation of channel is necessary. Post-translational modifications are considered to be some regulating mechanisms for PANX1, while PANX2, PANX3 have been uncharacterized to date. Through their significant evidences, PANXs exclude from gap junction and conduits ATP release and other cellular molecules from cells by various mechanisms. PANX1 is most extensive characterized and implicated in ATP signaling and inflammatory processes. Despite the constant advances, much significance of PANX1 in physiological processes remains elusive. Recently, various research groups along with our group have reported the Cryo-EM structure of Panx1 channel and uncovered the hidden functions in structure-function mechanism as well as to provide the clear understanding in physiological and pathophysiological roles. These research groups reported the novel heptameric structure with contains 4 transmembrane helices (TM), two extracellular loops and one intracellular loop with N and C terminus located at the intracellular side. In addition, the structure contains a large pore of which an inhibitor CBX act as a plug that blocking the passage of substrate. In this context, this review will present current mechanistic understanding in structure and function together with significant physiological roles particularly ATP release in health and disease. As such, this review emphasizes on recent functional properties associated with novel heptameric channel and demystifies channel-mediated ATP release function.