title: Intrinsic islet heterogeneity and gap junction coupling determine spatiotemporal Ca²⁺ wave dynamics.
abstract: Insulin is released from the islets of Langerhans in discrete pulses that are linked to synchronized oscillations of intracellular free calcium ([Ca(2+)]i). Associated with each synchronized oscillation is a propagating calcium wave mediated by Connexin36 (Cx36) gap junctions. A computational islet model predicted that waves emerge due to heterogeneity in β-cell function throughout the islet. To test this, we applied defined patterns of glucose stimulation across the islet using a microfluidic device and measured how these perturbations affect calcium wave propagation. We further investigated how gap junction coupling regulates spatiotemporal [Ca(2+)]i dynamics in the face of heterogeneous glucose stimulation. Calcium waves were found to originate in regions of the islet having elevated excitability, and this heterogeneity is an intrinsic property of islet β-cells. The extent of [Ca(2+)]i elevation across the islet in the presence of heterogeneity is gap-junction dependent, which reveals a glucose dependence of gap junction coupling. To better describe these observations, we had to modify the computational islet model to consider the electrochemical gradient between neighboring β-cells. These results reveal how the spatiotemporal [Ca(2+)]i dynamics of the islet depend on β-cell heterogeneity and cell-cell coupling, and are important for understanding the regulation of coordinated insulin release across the islet.
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee; Department of Bioengineering, University of Colorado, Aurora, Colorado; Barbara Davis Center, University of Colorado, Aurora, Colorado. Electronic address: richard.benninger@ucdenver.edu.
authors.forename: Richard K P
authors.initials: RK
authors.lastname: Benninger
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Troy
authors.initials: T
authors.lastname: Hutchens
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee.
authors.forename: W Steven
authors.initials: WS
authors.lastname: Head
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCaughey
authors.affiliation: Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Sylvain J
authors.initials: SJ
authors.lastname: Le Marchand
authors.affiliation: Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan; Brehm Diabetes Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee. Electronic address: dave.piston@vanderbilt.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D017629:Gap Junctions / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D013997:Time Factors
chemical_list: D005947:Glucose