Dataset Information

Calmodulin Binding to Connexin 35: Specializations to Function as an Electrical Synapse.

ABSTRACT: Calmodulin binding is a nearly universal property of gap junction proteins, imparting a calcium-dependent uncoupling behavior that can serve in an emergency to decouple a stressed cell from its neighbors. However, gap junctions that function as electrical synapses within networks of neurons routinely encounter large fluctuations in local cytoplasmic calcium concentration; frequent uncoupling would be impractical and counterproductive. We have studied the properties and functional consequences of calmodulin binding to the electrical synapse protein Connexin 35 (Cx35 or gjd2b), homologous to mammalian Connexin 36 (Cx36 or gjd2). We find that specializations in Cx35 calmodulin binding sites make it relatively impervious to moderately high levels of cytoplasmic calcium. Calmodulin binding to a site in the C-terminus causes uncoupling when calcium reaches low micromolar concentrations, a behavior prevented by mutations that eliminate calmodulin binding. However, milder stimuli promote calcium/calmodulin-dependent protein kinase II activity that potentiates coupling without interference from calmodulin binding. A second calmodulin binding site in the end of the Cx35 cytoplasmic loop, homologous to a calmodulin binding site present in many connexins, binds calmodulin with very low affinity and stoichiometry. Together, the calmodulin binding sites cause Cx35 to uncouple only at extreme levels of intracellular calcium.

SUBMITTER: Aseervatham J

PROVIDER: S-EPMC7504508 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Calmodulin Binding to Connexin 35: Specializations to Function as an Electrical Synapse.

Aseervatham Jaya J Li Xiaofan X Mitchell Cheryl K CK Lin Ya-Ping YP Heidelberger Ruth R O'Brien John J

International journal of molecular sciences 20200901 17

Calmodulin binding is a nearly universal property of gap junction proteins, imparting a calcium-dependent uncoupling behavior that can serve in an emergency to decouple a stressed cell from its neighbors. However, gap junctions that function as electrical synapses within networks of neurons routinely encounter large fluctuations in local cytoplasmic calcium concentration; frequent uncoupling would be impractical and counterproductive. We have studied the properties and functional consequences of ...[more]

PMID: 32882943

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Project description:In contrast to chemical transmission, few proteins have been shown associated with gap junction-mediated electrical synapses. Mixed (electrical and glutamatergic) synaptic terminals on the teleost Mauthner cell known as "Club endings" constitute because of their unusual large size and presence of connexin 35 (Cx35), an ortholog of the widespread mammalian Cx36, a valuable model for the study of electrical transmission. Remarkably, both components of their mixed synaptic response undergo activity-dependent potentiation. Changes in electrical transmission result from interactions with colocalized glutamatergic synapses, the activity of which leads to the activation of Ca(2+)/calmodulin-dependent kinase II (CaMKII), required for the induction of changes in both forms of transmission. However, the distribution of this kinase and potential localization to electrical synapses remains undetermined. Taking advantage of the unparalleled experimental accessibility of Club endings, we explored the presence and intraterminal distribution of CaMKII within these terminals. Here we show that (1) unlike other proteins, both CaMKII labeling and distribution were highly variable between contiguous contacts, and (2) CaMKII was not restricted to the periphery of the terminals, in which glutamatergic synapses are located, but also was present at the center in which gap junctions predominate. Accordingly, double immunolabeling indicated that Cx35 and CaMKII were colocalized, and biochemical analysis showed that these proteins associate. Because CaMKII characteristically undergoes activity-dependent translocation, the observed variability of labeling likely reflects physiological differences between electrical synapses of contiguous Club endings, which remarkably coexist with differing degrees of conductance. Together, our results indicate that CaMKII should be considered a component of electrical synapses, although its association is nonobligatory and likely driven by activity.

Dataset Information

Calmodulin Binding to Connexin 35: Specializations to Function as an Electrical Synapse.

Publications

Calmodulin Binding to Connexin 35: Specializations to Function as an Electrical Synapse.

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