Forsten K E, Lauffenburger D A
Department of Chemical Engineering, University of Illinois at Urbana-Champaign 61801, USA.
J Comput Biol. 1994 Spring;1(1):15-23. doi: 10.1089/cmb.1994.1.15.
Autocrine ligands regulate important cell behavioral functions in both physiological and pathological conditions. Binding of these ligands to cell-surface receptors involves more subtle considerations than that of exogenous (endocrine or paracrine) ligands. Autocrine secretion leads to a release of molecules in the local microenvironment proximal to the cell surface, thus allowing interaction with receptors to compete directly with diffusive loss to the bulk extracellular medium. Complications in autocrine systems due to this binding vs. transport competition arise in at least three aspects: (i) experimental measurement of autocrine ligand secretion rates is compromised; (ii) kinetics of autocrine ligand binding to cell-surface receptors are difficult to follow; and (iii) inhibition by exogenous blockers of autocrine ligand binding to cell receptors is problematic. At the heart of all these complications is the need to determine the fractional distribution of the secreted autocrine ligand between cell-surface receptor capture and diffusive loss to the bulk media. In this paper we offer a theoretical treatment of this problem using Brownian dynamics simulation techniques to calculate the capture probability of the cell receptors for the autocrine ligand. A major result is that the capture probability is significantly lower than the predicted by the Berg-Purcell steady-state diffusion approach. Another is that the capture probability is essentially independent of release location. Implications of these results for the complications found in autocrine systems are discussed.
自分泌配体在生理和病理条件下均调节重要的细胞行为功能。与外源性（内分泌或旁分泌）配体相比，这些配体与细胞表面受体的结合涉及更微妙的考量。自分泌分泌导致分子在细胞表面近端的局部微环境中释放，从而使与受体的相互作用能够直接与向细胞外介质的扩散损失相竞争。由于这种结合与转运竞争，自分泌系统中至少在三个方面出现了并发症：（i）自分泌配体分泌速率的实验测量受到影响；（ii）自分泌配体与细胞表面受体结合的动力学难以追踪；（iii）自分泌配体与细胞受体结合的外源性阻滞剂的抑制作用存在问题。所有这些并发症的核心在于需要确定分泌的自分泌配体在细胞表面受体捕获和向整体介质扩散损失之间的分数分布。在本文中，我们使用布朗动力学模拟技术对该问题进行了理论处理，以计算细胞受体对自分泌配体的捕获概率。一个主要结果是捕获概率显著低于伯格 - 珀塞尔稳态扩散方法的预测值。另一个结果是捕获概率基本上与释放位置无关。本文讨论了这些结果对自分泌系统中发现的并发症的影响。
