（封面圖片：作者建立的胰高血糖素調節(jié)模型,，背景中的胰島α細胞（紅色）表達囊泡谷氨酸轉運體（綠色）,，而β細胞分泌胰島素（藍色）。圖片提供：Nathan Bress）
生物谷報道：美國和瑞典科學家聯(lián)合在《細胞—代謝》（Cell Metabolism）上發(fā)表封面文章,，證實人類胰島α細胞能表達一種對于胰高血糖素的釋放非常關鍵的促離子型谷氨酸受體（ionotropic glutamate receptor iGluRs）,。
血糖穩(wěn)態(tài)（glucose homeostasis）的一個重要特征是胰島α細胞有效的釋放胰高血糖素（glucagon），胰高血糖素又被稱為抗胰島素或是胰島素B,。人類胰高血糖素是以N-末端組氨酸為起點,，C-末端蘇氨酸為終點的29個氨基酸組成的一條單鏈肽，分子量為3485,。其主要作用是對抗胰島素,，起著使血糖增加的作用。然而目前,，科學家對于調節(jié)胰高血糖素分泌過程的分子學機制還知之甚少,。
實驗中，研究人員分析了谷氨酸鹽（glutamate）作為正向自分泌信號在人類,、猴子,、小鼠胰島的胰高血糖素釋放過程中的作用。結果發(fā)現(xiàn),，谷氨酸鹽的正反饋極大的促進了胰高血糖素的分泌,，而一旦血糖濃度上升，胰高血糖素的分泌就會受到胰島素以及鋅離子或是γ-氨基丁酸（GABA）的限制,。
血糖濃度的下降能促使胰島α細胞釋放谷氨酸鹽,。谷氨酸鹽接著作用于AMPA和kainate型的促離子型谷氨酸受體，并使得細胞膜去極化,，鈣離子通道被打開,，最終使得細胞質中的自由鈣離子濃度增加，從而促進胰高血糖素的釋放,。在小鼠的活體實驗中,，阻礙促離子型谷氨酸受體將會降低胰高血糖素的釋放，并加劇胰島素導致的血糖過低癥狀,。因此,，谷氨酸鹽的自分泌反饋環(huán)路使得胰島α細胞具有了有效加強自身分泌活性的能力，這是在任何生理條件下保證充足的胰高血糖素釋放不可或缺的先決條件,。（生物谷www.bioon.com）
生物谷推薦原始出處：
Cell Metabolism,，Vol 7, 545-554, 04 June 2008，Over Cabrera, Per-Olof Berggren
Glutamate Is a Positive Autocrine Signal for Glucagon Release
Over Cabrera,1,2 M. Caroline Jacques-Silva,1 Stephan Speier,2 Shao-Nian Yang,2 Martin Köhler,2 Alberto Fachado,1 Elaine Vieira,3 Juleen R. Zierath,3 Richard Kibbey,4 Dora M. Berman,1 Norma S. Kenyon,1 Camillo Ricordi,1 Alejandro Caicedo,1, and Per-Olof Berggren1,2,
1 Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
2 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
3 Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
4 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
Corresponding author
Alejandro Caicedo
[email protected]
Corresponding author
Per-Olof Berggren
[email protected]
Summary
An important feature of glucose homeostasis is the effective release of glucagon from the pancreatic α cell. The molecular mechanisms regulating glucagon secretion are still poorly understood. We now demonstrate that human α cells express ionotropic glutamate receptors (iGluRs) that are essential for glucagon release. A lowering in glucose concentration results in the release of glutamate from the α cell. Glutamate then acts on iGluRs of the AMPA/kainate type, resulting in membrane depolarization, opening of voltage-gated Ca2+ channels, increase in cytoplasmic free Ca2+ concentration, and enhanced glucagon release. In vivo blockade of iGluRs reduces glucagon secretion and exacerbates insulin-induced hypoglycemia in mice. Hence, the glutamate autocrine feedback loop endows the α cell with the ability to effectively potentiate its own secretory activity. This is a prerequisite to guarantee adequate glucagon release despite relatively modest changes in blood glucose concentration under physiological conditions.
