A T1R-independent mechanism for responses to hyperosmotic sugars involves a carbonic anhydrase-sensitive mechanism in Type III receptor cells

Abstract

Recent findings from our laboratory demonstrated that the rostral nucleus of solitary tract (rNST) retains some responsiveness to glutamate (MSG+amiloride-MSGa) and sugars in mice lacking the canonical T1R receptors for these tastants. Here, we recorded from the parabrachial nucleus (PBN) in mice lacking the T1R1+T1R3 heterodimer (KO1+3), using warm stimuli to optimize sugar responses and employing extended concentrations and pharmacological agents to probe mechanisms. MSGa+IMP responses were not synergized in KO1+3 mice but responses to MSGa were similar to those in B6 (WT) mice. Glutamate responses in the neurons tested were unaffected by topical application of an mGluR4 antagonist. PBN T1R-independent sugar responses, including those to concentrated glucose, were more evident than in rNST. Sugar responses were undiminished by phlorizin, an inhibitor of SGLT, a component of a hypothesized alternative glucose-sensing mechanism. There were no sugar/umami "best" neurons in KO1+3 mice, and instead, sugars activated cells that displayed acid and amiloride-insensitive NaCl responses. In WTs, concentrated sugars activated "sugar/umami" cells but also electrolyte-sensitive neurons. The efficacy of hyperosmotic sugars for driving neurons broadly responsive to electrolytes implied an origin from Type III taste bud cells. To test this, we used the carbonic anhydrase (CA) inhibitor dorzolamide (DRZ), previously shown to inhibit amiloride-insensitive sodium responses arising from Type III cells. Dorzolamide had no effect on sugarelicited responses in WT sugar/umami PBN neurons but strongly suppressed them in WT and KO electrolyte-generalist neurons. These findings suggest a novel T1R-independent mechanism for hyperosmotic sugars, involving a CA-dependent mechanism in Type-III taste bud cells. Significance StatementSince the discovery of the Tas1r gene family that encodes receptors that lead to sweet and umami taste perception two decades ago, evidence has accrued that mice lacking these receptors maintain some degree of behavioral, physiological, and neural responsiveness to sugars and monosodium glutamate. But the basis for the remaining sensitivity to these nutritionally relevant compounds has remained elusive. Here we recorded from parabrachial nucleus taste neurons. Glutamate responses in mice lacking T1R1+T1R3 were unaffected by oral treatment of mGluR4 receptor antagonist suggesting that some T1R-independent glutamate responses are mediated by a different transduction pathway. Moreover, we identified a novel basis for T1R-independent responsiveness to hyperosmotic sugars that relies on carbonic anhydrase-mediated mechanism found in Type III taste bud cells.